Abstract
The extracellular matrix (ECM) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key signals to cardiomyocytes, vascular cells and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/anti-protease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review manuscript discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and non-fibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.
Keywords: heart failure, extracellular matrix, fibroblasts, collagen, matricellular gene
1. Introduction
The extracellular matrix (ECM) is a highly-dynamic non-cellular three-dimensional network that is present in all tissues, and plays a critical role in homeostasis and disease1. The ECM does not simply function as a mechanical support system that preserves tissue integrity, but also serves as a signaling hub that transduces cascades critical for cell function, and as a reservoir of growth factors that can be released following injury to modulate cell behavior and to activate a reparative program2. Organ homeostasis is critically dependent on the ECM network, as components of the matrix continuously interact with the cellular elements providing a stable structural support network, and coordinating cellular responses, in order to ensure functional integration of the cells. On the other hand, under conditions of stress, the ECM network may shield the cells from injurious stimuli, while serving as a key component in tissue repair, by orchestrating cellular responses. In many pathologic conditions, expansion of the ECM network or changes in the biochemical composition of matrix proteins contribute to the pathogenesis of disease either by directly perturbing normal organ structure and function, or by transducing maladaptive signals to the cells.
The adult mammalian heart is a syncytium comprised of cardiomyocytes and interstitial cells, enmeshed within a network of ECM proteins. Most myocardial diseases are associated with expansion of the cardiac interstitium, accompanied by marked alterations in the biochemical composition of the ECM network. The myocardial ECM does not simply serve as structural scaffold that determines the mechanical properties of the myocardium. Under conditions of stress, ECM macromolecules can drive cell biological responses with an important role in ventricular dysfunction and in the pathogenesis of heart failure.
It should be emphasized that human heart failure is pathophysiologically heterogeneous. Depending on the underlying etiology, several distinct pathophysiologic conditions, such as ischemia, volume and pressure overload, genetic factors, aging, and metabolic dysregulation may contribute to the pathogenesis of myocardial dysfunction. Animal model investigations suggest that the various pathophysiologic causes of heart failure trigger distinct ECM perturbation patterns that reflect the characteristics of the primary insult. For example, myocardial infarction (MI) rapidly activates a potent acute inflammatory response driven by necrotic cells, thus stimulating early ECM degradation. As the infarct is cleared from dead cells, suppression of inflammation and induction of growth factors favor activation of a fibrogenic program leading to formation of a scar. On the other hand, in the pressure-overloaded myocardium, mechanical stress stimulates release of neurohumoral mediators and activates mechanosensitive cascades, stimulating matrix-preserving pathways in cardiomyocytes and fibroblasts, in the absence of significant cellular necrosis. This response contrasts with the predominant disruption of the collagen network that has been described in the volume-overloaded myocardium (typically associated with valvular regurgitant lesions). This review manuscript discusses ECM-related mechanisms associated with the most common pathophysiologic conditions that cause heart failure, while attempting to identify unifying features that may link alterations of the ECM network and cardiac dysfunction.
2. The normal cardiac ECM
The cardiac ECM network is comprised of an interstitial component that surrounds all myocardial cells and forms a structural scaffold, and a pericellular component that is in close contact with certain cell types3. The basement membrane, a specialized form of ECM comprised of laminins, type IV collagens and proteoglycans is the predominant type of pericellular matrix and separates cardiomyocytes from the surrounding interstitial matrix4. Because the heart is perfused by a rich microvascular network, significant amounts of basement membrane ECM are also present in the interface between endothelial cells and pericytes. In mammalian hearts, the myocardial ECM network is organized on three interconnected levels: the epimysium encases the entire organ, the perimysium defines major bundles of myofibers, and the endomysium surrounds individual cardiomyocytes5,6. In addition to the intramyocardial (endomysial and perimysial) ECM network, significant amounts of matrix proteins are present in the adventitia of myocardial arteries and arterioles.
Early studies on the composition of the normal cardiac ECM focused predominantly on the collagens, the major structural components of the interstitial matrix7. Type I collagen predominantly forms thick rod-like fibers in the epimysium and perimysium and is the major structural component of the cardiac interstitium8,9. In contrast, type III collagen forms a fine network of fibers that is more prominent in the endomysium8,10,11. In addition to the fibrillar collagens, the cardiac ECM also contains glycosaminoglycans (such as hyaluronan), fibronectin, glycoproteins and proteoglycans, and serves as a reservoir for growth factors and proteases, which are stored in the interstitium, and can be released or activated following injury. Recent proteomic studies have revealed the remarkable complexity of the cardiac ECM network in health and disease12,13,14,15.
The role of the myocardial ECM as a mechanical scaffold that preserves cardiac geometry and facilitates force transmission seems intuitive. However, a growing appreciation of the interactions between matrix macromolecules and myocardial cells suggests that the cardiac ECM does not simply provide structural support, but may also transduce key signals regulating cardiomyocyte function. For example, the dystrophin glycoprotein complex serves as a molecular link between the contractile machinery of the cardiomyocytes and the surrounding ECM16. The transmembrane protein dystroglycan connects the cytoskeletal components of the cardiomyocytes to the ECM through interactions with the α2 chain of laminin 217,16, playing an important role in cardiac homeostasis. Unfortunately, very little is known regarding the role of specific ECM-dependent molecular pathways in mediating the coordinated contraction of cardiomyocytes in normal hearts. In addition to their effects in contractile function, ECM proteins may also interact with cardiomyocytes, vascular cells and interstitial cells in order to transduce survival signals18.
3. The link between the ECM and cardiac dysfunction: the significance of cardiac fibrosis.
Although the ECM remains inconspicuous in health, it takes center stage in myocardial disease, as the cardiac interstitium undergoes dramatic and dynamic changes that have a major impact on cardiac function. The term “cardiac fibrosis” is used to describe the expansion of the ECM network that accompanies most forms of myocardial disease19. Using simple histopathologic analysis, three forms of cardiac fibrosis can be recognized, reflecting distinct mechanisms of fibrotic remodeling. The term “replacement fibrosis” describes the formation of a scar in areas of myocardial necrosis, represents the end-result of a reparative process in response to primary cardiomyocyte injury, and reflects the negligible regenerative capacity of adult mammalian cardiomyocytes. Replacement fibrosis is typically the result of MI20. In contrast, a wide range of injurious stimuli, including a pressure load, metabolic dysfunction and aging may cause “interstitial fibrosis”, widening the endomysium and perimysium due to deposition of structural ECM proteins, or “perivascular fibrosis”, leading to expansion of the peri-adventitial collagenous area in the cardiac microvasculature. Interstitial and perivascular fibrotic lesions may not be driven by cardiomyocyte death. Whether perivascular and interstitial fibrotic changes have distinct functional consequences remains unknown. In heart failure patients, periadventitial microvascular fibrosis has been associated with reduced coronary blood flow21, and may perturb coronary vasodilatory responses22, thus exacerbating the imbalance between supply and demand under conditions of stress23.
Robust clinical evidence suggests a strong association between expansion of the cardiac ECM and adverse outcome in patients with heart failure. In heart failure with reduced ejection fraction (HFrEF) patients, the severity of fibrosis predicts death and adverse cardiac events24. On the other hand, heart failure with preserved ejection fraction (HFpEF) patients typically exhibit expansion of the interstitial ECM network, associated with coronary microvascular rarefaction and inflammatory activation25,26. In subjects with HFpEF, interstitial ECM expansion is associated with increased mortality and higher hospitalization rates27. Although the prognostic significance of cardiac ECM deposition in heart failure is well-documented, whether worse outcome in patients with extensive fibrotic lesions is due to the adverse consequences of fibrosis, or simply reflects a more pronounced reparative response to more severe primary cardiomyocyte injury is unclear. Several mechanisms may contribute to direct adverse effects of ECM expansion and/or remodeling on both systolic and diastolic function. First, accentuated deposition of cross-linked collagen in the cardiac interstitium may increase myocardial stiffness, resulting in diastolic dysfunction. Second, ECM deposition may promote systolic dysfunction by perturbing the coordination of myocardial excitation-contraction coupling. Third, expansion of the peri-adventitial ECM may disrupt cardiomyocyte perfusion. Fourth, perturbations in the protease/anti-protease balance in the cardiac interstitium may trigger degradation of fibrillar collagens, thus disrupting ECM-dependent pathways that regulate cardiomyocyte contraction, and leading to systolic dysfunction28. Moreover, perturbations in the matrix network may also deprive cardiomyocytes from crucial pro-survival signals transduced by intact ECM proteins18, 29. Fifth, generation of ECM fragments may activate pro-inflammatory pathways, recruiting immune cells to the interstitium and leading to cardiomyocyte dysfunction and death30.
The relation between perturbations in the cardiac ECM network and adverse outcome may also involve an increased incidence of arrhythmic events and conduction abnormalities. ECM deposition disrupts propagation of the and often results in generation of re-entry circuits 31. The cellular composition of the fibrotic lesions and the ECM profile of the cardiac interstitium may play an important role in determining arrhythmogenicity in failing hearts32. It should be emphasized that changes in the ECM network may have an impact in geometry and function of all cardiac chambers. Changes in the right ventricular matrix may contribute to the morbidity and mortality in patients with pulmonary hypertension33. Atrial ECM remodeling and fibrosis are implicated in the pathogenesis and complications of atrial tachyarrhythmias34.
4. The ECM network in the pathogenesis of heart failure.
Heart failure is characterized by remarkable pathophysiologic heterogeneity. The patterns of ECM perturbations, and the relative role of matrix macromolecules in the pathogenesis of heart failure are dependent on the type and duration of myocardial injury. Pressure overload, volume overload. ischemic injury, diabetes obesity and metabolic dysregulation, are associated with distinct patterns of ECM alterations.
4.1. The ECM in heart failure associated with pressure overload
4.1.1. Cellular effectors of ECM remodeling in the pressure-overloaded heart
Left ventricular pressure overload is the predominant pathophysiology in systemic hypertension and in conditions associated with left ventricular outflow obstruction (such as aortic stenosis), and leads to progressive development of heart failure35,36. In both animal models of left ventricular pressure overload, and in human patients with sustained pressure loads, early development of cardiac hypertrophy initially serves as an adaptive response that preserves cardiac output37. However, prolonged pressure overload triggers fibrosis and perturbs cardiomyocyte relaxation, increasing myocardial stiffness and causing diastolic dysfunction. Persistent pressure overload eventually results in dilative remodeling and systolic dysfunction. Extensive evidence suggests that the changes in the myocardial ECM network in response to pressure overload not only increase passive stiffness by altering the mechanical properties of the ventricle, but also play a critical role in regulating inflammatory, fibrotic and hypertrophic cellular responses. Although cardiac fibroblasts are considered essential modulators of the matrix network following pressure overload, several other cell types, including immune cells, vascular cells and cardiomyocytes have been implicated in ECM remodeling either directly (by secreting proteases or anti-proteases with a critical role in matrix metabolism) or indirectly (by modulating fibroblast phenotype) (Figure 1).
Figure 1. The cellular effectors of ECM remodeling in the pressure-overloaded heart.
Mechanical stress triggers transduction of mechanosensitive signaling cascades, activates TGF-β and stimulates neurohumoral mediator release (such as angiotensin, aldosterone and norepinephrine). Fibroblasts are the main effectors of ECM expansion, producing both structural and matricellular ECM proteins. Activated myofibroblasts in the pressure-overloaded heart predominantly originate from local resident fibroblasts, other interstitial cells, such as cardiac pericytes, may also undergo myofibroblast conversion (blue arrows). Other cell types (such as endothelial cells) appear to have very limited direct contributions to the myofibroblast population in the remodeling myocardium. Cardiomyocytes, immune cells and vascular cells are important regulators of ECM remodeling. Mechanical stress triggers synthesis of pro-inflammatory mediators in cardiomyocytes, promoting recruitment of lymphocytes and macrophages. Activated endothelial cells also participate in recruitment of immune cells. Macrophages and lymphocytes may promote fibroblast activation by secreting growth factors (such as TGF-βs). All myocardial cells are capable of producing proteases, involved in ECM remodeling.
Fibroblasts and myofibroblasts
Expansion and activation of fibroblasts is consistently noted in experimental models of cardiac pressure overload38,39. Activated fibroblasts typically undergo myofibroblast conversion, expressing contractile proteins, such as α-smooth muscle actin (α-SMA)38 and the embryonic isoform of smooth muscle myosin heavy chain40, and synthesizing large amounts of structural and matricellular ECM proteins41. Although some investigations have suggested that endothelial cells42 and circulating fibroblast progenitors may undergo fibroblast conversion, recent lineage tracing studies demonstrated that resident fibroblast populations are the main cellular source of activated myofibroblasts in the pressure-overloaded myocardium43,44. Activation of fibroblasts in response to mechanical stress likely involves several distinct mechanisms45. First, fibroblasts sense increased mechanical load through activation of surface integrins46,47,48 syndecans49, and mechanosensitive membrane channels50,51. Subsequent stimulation of mechanosensitive intracellular signaling cascades, such as the RhoA/ROCK52,53, Focal Adhesion Kinase (FAK)54,55.56 and Mitogen-activated protein kinase (MAPK)39 pathways may promote a fibrogenic program through activation of the transcription factor myocardin-related transcription factor (MRTF)57,58. Second, mechanical stress has been linked with integrin-dependent activation of transforming growth factor (TGF)-β59, a critical mediator in myofibroblast conversion that triggers integrin synthesis in cardiac fibroblasts60 and promotes activation of a matrix-synthetic and matrix-preserving program61,30. Third, pressure overload may trigger systemic and local activation of the renin-angiotensin-aldosterone system (RAAS), stimulating fibroblast proliferation and ECM protein synthesis through Angiotensin II type 1 receptor (AT1R) signaling. Fourth, pressure overload induces expression of fibroblast-specific microRNAs that activate MAPK signaling in fibroblasts promoting expansion of the interstitial ECM62. The potential link between mechanical stress and a fibrogenic microRNA profile has not been investigated. Fifth, activation of fibroblasts in the pressure overloaded heart may require mechanosensitive activation of other cell types, including immune cells, vascular cells and cardiomyocytes.
Immune cells
Macrophages63,64,65 lymphocytes66,67,68 and mast cells69,70 have been implicated in the fibrotic response in the pressure-overloaded heart (Figure 2). Although immune cells do not produce significant amounts of structural ECM proteins and do not undergo conversion to fibroblasts43, they may function as key effectors of ECM expansion in the pressure overloaded myocardium by releasing fibrogenic mediators70 and matricellular proteins71, or by transducing adhesion-dependent fibrogenic signals to cardiac fibroblasts68. Moreover, immune cell subpopulations may directly remodel the cardiac ECM by secreting matrix metalloproteinases (MMPs), or other matrix-degrading proteases72. What is the central mechanism that activates immune cells in the pressure-overloaded myocardium? First, macrophages and lymphocytes may respond directly to mechanical stress, activating a fibrogenic program. Mechanical stress has been suggested to stimulate T lymphocyte-driven inflammation that may stimulate fibrogenic signaling73. Macrophages may also sense mechanical cues to alter their level of activation74. Expression of mechanosensitive ion channels (such as Transient receptor potential cation channel subfamily V member 4/TRPV4) has been observed in macrophages and may modulate their functional properties75, promoting a fibrogenic phenotype. Second, resident myocardial immune cells may acquire a fibrogenic profile in response to the local or systemic release of neurohumoral mediators or fibrogenic growth factors. Moreover, in vivo studies have suggested that mineralocorticoid receptor signaling in myeloid cells promotes a fibrogenic macrophage phenotype65, that is critical for expansion of the interstitial ECM in models of hypertensive heart disease76,77 or left ventricular pressure overload65. Mineralocorticoid receptor-mediated activation of lymphocytes has also been implicated in the pathogenesis of interstitial fibrosis in the pressure-overloaded heart78. Third, fibrosis in the pressure-overloaded heart may reflect new recruitment of fibrogenic immune cells, mediated through pro-inflammatory activation of the microvascular endothelium79,80, or through paracrine actions of cardiomyocytes81.
Figure 2. The link between immune cell infiltration and ECM expansion in the pressure-overloaded heart.
Serial sections from a mouse heart undergoing transverse aortic constriction for 7 days stained with hematoxylin+eosin (H&E), the macrophage marker Mac2 and Sirius red (to label collagen fibers) show periadventitial infiltration with abundant macrophages in areas of perivascular fibrosis (arrows). Original data and images reported in our published work83.
It should be noted that not all studies support the importance of inflammatory cells in pressure overload-induced heart failure. Macrophage depletion using a genetic model did not affect the progression of myocardial remodeling in mice with established pressure overload-induced heart failure82.
Vascular cells
The impressive perivascular ECM deposition in pressure-overloaded hearts (Figure 2)83 suggests that vascular cells may be important contributors to the cardiac fibrotic response. Some experimental studies have suggested that endothelial cells may contribute to ECM remodeling in the pressure-overloaded heart by undergoing endothelial to mesenchymal transition (EndMT)42, thus acquiring a fibroblast-like phenotype. However, this notion was refuted by robust lineage tracing studies44 that reported very low numbers of endothelial-derived fibroblasts in the remodeling myocardium84. Endothelial cells may activate fibroblasts by secreting pro-fibrotic mediators, such as TGF-β1, fibroblast growth factors (FGFs), or endothelin-185, or by facilitating recruitment of fibrogenic immune cell subpopulations through expression of adhesion molecules and chemokines79.
The role of cardiac pericytes in matrix deposition and metabolism following pressure overload remains poorly documented. This is due, at least in part, to challenges in identification and characterization of cardiac pericyte populations. Pericytes may contribute to ECM remodeling through conversion to activated myofibroblasts86, or through secretion of fibroblast-activating growth factors.
Cardiomyocytes
Mechanical stress activates a pro-inflammatory and fibrogenic gene expression program in cardiomyocytes through a pathway that has been suggested to involve angiotensin II-induced stimulation of CaMKIIδ87,81. In a mouse model of deoxycorticosterone/salt-induced cardiac remodeling, cardiomyocyte-specific mineralocorticoid receptor signaling mediated expansion of the ECM network88. Growth factors released and activated in response to mechanical stress may also activate a fibrogenic profile in cardiomyocytes. In a model of left ventricular pressure overload, TGF-β receptor II signaling in cardiomyocytes was found to contribute to the development of cardiac fibrosis 89.
4.1.2. ECM proteins in the pressure-overloaded myocardium
Fibrillar collagens
Fibrillar collagens90 constitute a subgroup within the collagen family whose members confer mechanical strength and support tissue organization in many organs. In addition to their structural role, fibrillar collagens may also interact with cell surface receptors, transducing signals. Increased deposition of fibrillar collagens by activated cardiac fibroblasts is consistently noted in pressure-overloaded hearts. Table 1 summarizes our knowledge on the expression and role of fibrillar collagens in failing hearts.
Table 1:
Fibrillar collagens in the heart
| Fibrillar collagen | Cardiac localization | Role in cardiac homeostasis | Changes in hypertensive heart failure | Changes in ischemic heart failure | Changes in other myocardial conditions |
|---|---|---|---|---|---|
| Col I | Col I is the predominant fibrillar collagen in adult mammalian hearts. | Thick Col I fibers may preserve cardiac geometry and structure, and regulate compliance, while contributing to force transmission. Mice with a mutation in the proa2(I) chain have a more compliant ventricle upon passive inflation276 | Both Col I and Col III are overexpressed in pressure-overloaded hearts277. Predominance of Col I was associated with increased stiffness in some human and experimental studies99,100. However, in SHR hearts, myocardial stiffness was not associated with changes in Col I:Col III ratio, but was rather attributed to crosslinking101. Moreover, in human patients with aortic stenosis, comparable induction of Col I and III was noted102 | In the rat model of MI, a greater increase in Col I in non-infarcted myocardium278. In rats undergoing infarction protocols Col III levels seemed to increase earlier in the infarcted heart279,197 |
In patients with DCM, increased Col I: Col III ratio may be associated with reduced myocardial compliance280. Inflammatory cardiomyopathy was associated with a higher proportion of Col III281. Conflicting findings on the effects of aging have been reported. Col I was highly expressed in neonatal hearts282, whereas Col III was increased with aging283. In other studies, aging was associated with increased number and thickness of Col I fibers230 |
| Col III | Significant amounts of Col III are found in normal hearts. The ratio of Col III:Col I is dependent on species and age284. | Col III forms a thin network of fibers more prominent in the endomysium.A higher Col III:Col I ratio has been associated with increased elasticity | |||
| Col V | Expressed in developing valves and in fetal myocardium. In adult rat hearts Col V immunoreactivity was reported in the vascular matrix285. | Col V regulates collagen fibril diameter and assembly in the valves and in the left ventricular myocardium286. | Increased levels of Col V have been reported in pressure-overloaded rat myocardium287,288. | Col V immunoreactivity was reported in the peri-infarct region in a rat model of infarction285. Increased ColVα2 was found in proteomic analysis of the cardiac ECM of ischemic and reperfused porcine hearts15. | Autoantibodies against Col V have been suggested to play a role in antibody-mediated cardiac allograft rejection, or allograft vasculopathy289 |
| Col XI | Col XI is expressed in developing heart valves, in the supporting apparatus and in left ventricular trabeculae286. | Col XI regulates collagen fibril assembly predominantly in the valves286. | N/A | Not found to be upregulated in porcine model of I/R15 | N/A |
| Col XXIV | Col XXIV is involved in Col I fibrillogenesis in the developing bone and eye290 Col24a1 mRNA expression not found in mouse myocardium291. | N/A | N/A | Not found to be upregulated in a model of porcine I/R15. | N/A |
| Col XXVII | Col XXVII is transiently expressed in developing coronary vessels292. It is localized in fine fibrillar structures independent of classical collagen fibrils. In adult mice its expression is restricted to cartilage. | N/A | N/A | N/A | N/A |
DCM, dilated cardiomyopathy, SHR: spontaneously hypertensive rats, N/A: no information available.
Activation of a matrix-synthetic phenotype in cardiac fibroblasts may involve neurohumoral mediators (such as angiotensin II and aldosterone), and growth factors (such as TGF−βs)91. ACE inhibition, AT1R blockade and mineralocorticoid antagonism attenuated collagen deposition in most92,93,94, but not all95 experimental studies in models of left ventricular pressure overload. In contrast to the fibrogenic actions of the AT1R, the angiotensin II type 2 receptor (AT2R) may play an inhibitory role96, attenuating fibroblast proliferation and reducing ECM deposition in models of hypertension97. To what extent the beneficial effects of ACE inhibition and AT1R blockade in human patients with heart failure are due to attenuated ECM expansion remains unclear.
It has been suggested that the relative amount of collagen I vs. collagen III fibers may regulate myocardial compliance in remodeling hearts. Collagen I forms thicker and stiffer fibers, whereas the finer reticular collagen III fibers are more compliant and increase elasticity. In models of hypertensive cardiac fibrosis, type I collagen exhibits more intense and prolonged upregulation than collagen III98. Thus, it is attractive to suggest that the predominance of type I fibers in the pressure-overloaded myocardium may mediate diastolic dysfunction. This notion is supported by some associative evidence. High levels of type I collagen was associated with increased myocardial stiffness in some human and experimental studies99,100. Moreover, ACE inhibition has been suggested to reduce the myocardial type I to type III collagen ratio in models of hypertension98. However, other studies did not support an important role of the collagen type profile in the pathogenesis of diastolic dysfunction. In hypertensive rats, myocardial stiffness was not associated with changes in collagen I/III ratio, but was rather attributed to crosslinking101. Moreover, in human patients with aortic stenosis, comparable induction of collagen type I and type III was noted102. The technical challenges in assessment of collagen I and III levels in the myocardium may explain, at least in part, the conflicting findings.
Increased synthesis of procollagens transcripts by activated myofibroblasts is followed by secretion of soluble procollagens into the extracellular space. Once outside the cells, procollagen chains are processed, assembled into fibrils, and cross-linked. Very limited information is available on the molecular steps regulating collagen processing and maturation in pressure-overloaded hearts. Cleavage of the N- and C-terminal propetides attached to procollagen is a critical part of collagen processing. A study in a model of left ventricular pressure overload demonstrated that the enhancer protein Procollagen C-Endopeptidase Enhancer 2 (PCOLCE2) regulates C-terminal propetide cleavage by enhancing the activity of the C proteinase bone morphogenetic protein (BMP)1103. The matricellular protein SPARC (secreted protein acidic and rich in cysteine) also contributes to post-synthetic processing of collagen in the pressure-overloaded heart and increases diastolic stiffness104
Collagen crosslinking plays an important role in regulation of geometric remodeling and dysfunction in the pressure-overloaded heart. Several crosslinking enzymes are upregulated in the remodeling myocardium, including members of the lysyl oxidase (LOX) family105,106 and transglutaminase-2 (TG2, also known as tissue transglutaminase)107,108. In addition to its transamidase-dependent enzymatic actions, TG2 bind to the ECM and may also act as a signaling molecule modulating fibroblast-mediated MMP and tissue inhibitor of metalloproteinases (TIMP) synthesis through non-enzymatic mechanisms109. Studies in human patients support the significance of collagen crosslinking in the pathogenesis of heart failure. In hypertensive patients with heart failure the degree of crosslinking and not the total amount of collagen was associated with elevated filling pressures110. Moreover, in patients with hypertensive heart failure, increased collagen crosslinking assessed through endomyocardial biopsy was associated with a higher incidence of hospitalizations111. However, preservation of geometry and function in the myocardium likely requires some matrix crosslinking activity. In models of cardiac pressure overload was associated with reduction in myocardial collagen crosslinking112.
Non-fibrillar collagens
Non-fibrillar collagens do not form large fibrillar bundles, but can associate with type I and type III collagen fibrils to regulate anchoring, networking and organization of the ECM113 Moreover, non-fibrillar collagens may bind to cell surface receptors, modulating cellular phenotype, or yield bioactive fragments that regulate cellular responses. On the basis of their structural properties and functions, non-fibrillar collagens are classified into 6 groups (Table 2). Unfortunately, the information available on the role of non-fibrillar collagens in remodeling of the pressure-overloaded heart is limited. Table 2 summarizes our current understanding on the expression patterns and role of non-fibrillar collagens in heart failure.
Table 2:
Non-fibrillar collagens in heart failure
| Subfamily | Member | Cardiac localization and role in myocardial homeostasis | Role in non-ischemic heart failure | Role in MI and in ischemic heart failure |
|---|---|---|---|---|
| Network-forming Collagens (IV, VIII, X) | IV | Col IV is a major component of the basement membrane that surrounds cardiomyocytes and contributes to the vascular structure in the myocardium. Col IV is produced by both cardiomyocytes and interstitial cells293. Col IV may mediate homeostatic functions in cardiomyocytes and vascular cells through activation of integrin signaling. Col IV-derived peptides (such as canstatin) have been implicated in regulation of cardiomyocyte L type Ca2+ channel activity294 | Col IV induction has been observed in many cardiomyopathic conditions295,296 and in diabetic and aging hearts297,298 Collagen IV-derived peptide canstatin may regulate angiogenesis, fibroblast migration, and cardiomyocyte survival in failing hearts299. | Col IV is upregulated in the infarct border zone in experimental models of MI300 |
| VIII | Col VIII is expressed transiently during cardiogenesis. Low levels of Col VIII expression are noted in normal adult hearts301. | In the pressure-overloaded myocardium Col VIII expression is reduced in animals with decompensated heart failure302. Endogenous Col VIII has been implicated in activation of myofibroblasts and may protect the heart from dilation 119. | N/A | |
| X | Col X is expressed predominantly in cartilage. Expression in valve leaflets from patients with aortic stenosis has been reported303. | N/A | N/A | |
| FACITs (IX, XII, XIV, XVI, XIX, XX, XXI, XXII) | IX | Col IX is co-distributed with Col II in cartilage, and eye and inner ear. Transient Cola1IX mRNA expression has been reported in developing hearts.304 | N/A | N/A |
| XII | Col XII expression has been detected in the epicardium of zebrafish305. Col XII mRNA expression has been reported in human hearts306. | N/A | In zebrafish, epicardial expression of Col XII was increased following cryoinjury305 | |
| XIV | Col XIV is highly expressed in embryonic hearts, and regulates collagen fibril organization, cardiomyocyte proliferation and fibroblast survival307. | N/A | Col XIV was overexpressed in reperfused porcine MI15. | |
| XVI | An immunohistochemical study suggested expression of col XVI in developing and adult mouse hearts308. | N/A | N/A | |
| XXI | Col XXI mRNA expression has been reported in adult human hearts, predominantly localized in the right atrium and ventricle309 | N/A | N/A | |
| XXII | Col XXII expression was found in the mammalian myocardium localized at insertion points of the chordae tendinae to the myocardium310 | N/A | N/A | |
| MACITs (XIII, XVII, XXIII, XXV) | XIII | Col XIII,a transmembrane collagen, is expressed in the intercalated discs of the adult heart311. Transgenic overexpression of Col XIII caused fetal lethality, associated with myocardial defects and dysfunction312,313. | N/A | N/A |
| XVII | Col XVII expression has been reported in developing and adult mouse hearts and is a component of hemidesmosomes314 | N/A | N/A | |
| XXIII | Col XXIII mRNA expression was found in developing mouse hearts315 | N/A | N/A | |
| XXV | Although Col XXV is predominantly expressed in the brain, weak expression in the developing heart has been suggested316 | N/A | N/A | |
| Anchoring fibrils (VII) | VII | Col VII is predominantly expressed in the dermal-epidermal junction. Cardiac expression has not been systematically studied. | A subset of patients with dystrophic epidermolysis bullosa ( a condition caused by ColVII mutations) exhibit dilated cardiomyopathy317,318. | N/A |
| Beaded filament forming collagens (VI, XXVI, XXVIII) | VI | Col VI is highly expressed in developing and adult hearts319,320. In adult mammals, col VI represents ~5% of total collagen and is broadly distributed in the endomysium and in the media and adventitia of myocardial vessels 8. However, Col VI KO mice had no significant baseline cardiac defects120 and patients with Bethlem myopathy, a condition associated with col VI mutations321 do not seem to exhibit myocardial disease322. | Increased co VI deposition has been reported in many cardiomyopathic conditions 323. Patients with DCM exhibit increased Col VI deposition, localized in the perivascular and interstitial space324, and within t-tubules320. Considering its role in myofibroblast activation118, col VI may be involved in fibrosis of the pressure-overloaded heart. |
Following infarction, Col VI was found to play a protective role, limiting infarct size and attenuating adverse remodeling120. The protective actions may involve effects on cardiomyocyte survival and on activation of reparative myofibroblasts118. |
| XXVIII | Col XXVIII mRNA was detected in neonatal mouse hearts, but not in adult hearts 325. | N/A | N/A | |
| MULTIPLEXIN (XV, XVIII) | XV | Col XV is expressed in developing and adult hearts326,327 and plays a crucial role in cardiac homeostasis. Col XV null mice developed a cardiomyopathy, associated with increased vascular permeability, defective interstitial network formation, and perturbed organization of cardiomyocytes328 | Col XV loss was associated with exercise-induced myocardial injury329, presumably due to protective actions of Col XV on stressed cardiomyocytes and vascular cells. Pressure-overloaded mouse hearts exhibited increased Col XV deposition328. |
N/A |
| XVIII | Collagen XVIII is highly expressed in embryonic and adult hearts330,331. However, genetic loss of ColXVIIIa1 did not have any functional consequences in mouse hearts, despite basement membrane alterations in atrioventricular valves332. Proteolytic cleavage of Col XVIII within its C-terminal domain yields release of endostatin, an endogenous inhibitor of angiogenesis. | In patients with chronic heart failure, circulating endostatin levels may predict adverse outcome333. | Myocardial ischemia triggers endostatin release due to Col XVIII cleavage334. Endostatin is a potent inhibitor of angiogenesis121, and endostatin levels inversely correlate with collateral formation in patients with ischemic heart disease335. However, in a model of MI, endostatin neutralization had adverse effects suggesting protective actions of Col XVIII, presumed due to anti-fibrotic actions, and to inhibition of protease activity336 |
FACIT, fibril-associated collagens with interrupted triple helices; MACIT, membrane-associated collagens with interrupted triple helices; MULTIPLEXIN, multiple triple-helix domains and interruptions.
Fibrogenic growth factors (such as TGF-β) and neurohumoral mediators (such as angiotensin II) implicated in induction and secretion of fibrillar collagens are also capable of inducing synthesis of several members of the non-fibrillar collagen subfamilies (such as collagen IV, VI and VIII)114,115. Thus, in fibrotic pressure-overloaded hearts, deposition of collagens I and III may be accompanied by concomitant upregulation of non-fibrillar collagens that may play an important role in organization of the ECM and in activation of cardiac interstitial cells116,117. In vitro, collagen VI has been identified as a potent stimulus for myofibroblast conversion118, whereas collagen VIII may activate ECM expansion by promoting fibroblast migration and by enhancing TGF-β synthesis119. In vivo, loss of collagen VIII was associated with reduced infiltration of the pressure-overloaded heart with myofibroblasts and attenuated fibrosis. These anti-fibrotic effects were associated with increased mortality and left ventricular dilation, supporting the importance of matrix-preserving actions in protecting the heart from adverse remodeling119. The cellular mechanisms for the effects of non-fibrillar collagens in the remodeling heart may not be limited to fibroblast activation, but may also involve actions on cardiomyocyte survival, inflammatory cell activation and vascular cell function120. Several non-fibrillar collagens can be cleaved following injury, generating bioactive fragments with important biological functions. For example, collagen IV-derived peptides (such as canstatin) have been suggested to regulate cardiomyocyte survival, fibroblast migration and angiogenesis in failing hearts115. Moreover, endostatin a collagen XVIII-derived peptide is a potent endogenous inhibitor of angiogenesis121 that may play an important role in regulation of cellular responses in failing hearts.
Specialized matrix proteins
Remodeling of the pressure-overloaded myocardium is associated with secretion and deposition of specialized ECM proteins, which are not part of the normal adult cardiac matrisome and do not play a primary structural role, but are induced under conditions of stress and transduce molecular signals in cardiomyocytes and interstitial cells, modulating important cellular responses. Increased expression of embryonic isoforms of cellular fibronectin, matricellular proteins and extracellular proteoglycans has been extensively documented in animal models of cardiac pressure overload and in failing human hearts122,123,124. In failing and remodeling hearts, the ECM is enriched with a broad range of macromolecules that modulate growth factor and protease activity, or bind to cell surface receptors, regulating cell survival, proliferation and gene expression. Mechanotransductive signaling, TGF-βs, and neurohumoral mediators (such as angiotensin II) are potent inducers of specialized ECM proteins in the pressure-overloaded heart.
Fibronectin
Cardiac pressure overload triggers marked upregulation of splice variants of fibronectin (Fn) that contain the extra domain A (ED-A+Fn), or the extra domain B (ED-B+Fn)125. ED-A fibronectin has been suggested to co-operate with TGF-β, stimulating myofibroblast conversion in vitro and in vivo126,127,128. The molecular mechanism responsible for the interaction between ED-A+Fn and TGF-β remains poorly understood. In vitro experiments suggest that ED-A+Fn may bind to Latent TGF-β−Binding Protein (LTBP)-1, contributing to the spatial localization of activatable TGF-β in tissues129. On the other hand, the role of ED-B+Fn, in heart failure is unclear. ED-B deficient fibroblasts exhibit slow growth and have attenuated synthesis of ECM proteins130. Whether induction of ED-B+Fn in the pressure overloaded myocardium mediates fibroblast activation has not been investigated. Polymerization of fibronectin following secretion plays a critical role in regulation of fibroblast phenotype and increases the tensile strength of collagen fibers131,132.
Matricellular proteins
Tissue remodeling is associated with induction of a wide range of extracellular macromolecules that bind to the structural ECM, interact with growth factors and proteases, and modulate signaling responses in many cell types by binding to cell surface receptors, such as integrins and syndecans. These proteins, termed “matricellular” do not play a primary structural role, but serve as a molecular bridge between the ECM and the cells, acting as dynamic integrators of microenvironmental changes and as essential mediators of tissue remodeling122,133,134,135. The “founding members” of the matricellular family were tenascin-C, SPARC, and thrombospondin (TSP)-1; however recognition of the complexity of matrix responses following injury resulted in rapid expansion of the family with the inclusion of several additional proteins, such as TSP-2 and −4, tenascin-X, osteopontin, periostin, the fibulins, and the members of the CCN family. In vivo studies have revealed a remarkable functional complexity of matricellular proteins, reflecting the contextual nature of their effects that depend on the various structural proteins, cytokines, and growth factors they associate with, and the cell types with which they interact in different tissues, and in various pathologic conditions.
Cardiac pressure overload induces marked induction and interstitial deposition of several members of the matricellular family122. In the remodeling myocardium, cardiomyocytes, fibroblasts, immune cells, and vascular cells, all major cellular effectors of fibrosis, have been identified as important targets of the matricellular proteins. Table 3 summarizes our knowledge on the expression and role of the major members of the matricellular family in heart failure. Although each member has a unique repertoire of functional effects and molecular interactors, several common themes have emerged regarding their cell biological actions. First, several matricellular proteins have been implicated in regulation of fibroblast proliferation, survival and activation, and in myofibroblast conversion136,137,41,138,139.140 Thus, in pressure overloaded hearts, matricellular proteins, such as TSP-1 (Figure 3), TSP-4, periostin and osteopontin may act by stimulating a fibrogenic program in cardiac fibroblasts. Although most members of the family have been suggested to exert fibrogenic actions in vivo, matricellular actions that inhibit fibroblast responses, or contribute to resolution of fibrosis have also been reported141. Second, immune cell subpopulations are increasingly recognized as important cellular targets of matricellular proteins. For example, tenascin-C (Figure 4) may act as an important modulator of macrophage phenotype in remodeling pressure-overloaded hearts142,143,144. Third, some matricellular proteins may have direct actions on cardiomyocyte survival under conditions of stress145,146. Fourth, although the traditional definition of a matricellular protein implies absence of a structural role, several members of the matricellular family (such as SPARC, TSP-1 and TSP-2) have been implicated in collagen fibril assembly and in regulation of ECM cross-linking147,104,148.
Table 3:
Expression, role and mechanisms of action of the major members of the matricellular family in heart failure
| Matricellular protein | Expression and role in non-ischemic cardiomyopathy | Expression and role in MI and in ischemic cardiomyopathy | Proposed mechanisms of action |
|---|---|---|---|
| TSP-1 |
Expression: Transiently upregulated and deposited in the interstitial and perivascular ECM in models of LV pressure overload136,337. Upregulated in perivascular areas in diabetic hearts217. Role: Has been reported to protect the pressure-overloaded myocardium from dysfunction by stabilizing the ECM136. The TSP-1/TGF-β axis has been reported to promote fibrosis and dysfunction in the diabetic pressure overloaded heart337. The TSP-1/CD47 axis has been suggested to promote heart failure in a model of pressure overload338 Mediates capillary rarefaction in diabetic hearts217 |
Expression: Transiently induced in the infarct border zone199. Role: Protects from adverse remodeling, limiting expansion of the inflammatory infiltrate199. |
i) Activation of TGF-β, may promote myofibroblast conversion and acquisition of a matrix-synthetic phenotype337,199. ii) Inhibition of MMPs136 iii) Interaction with collagens and LOX precursors147 iv) Angiostatic effects217. v) anti-inflammatory actions199 vi) TSP-1/CD47 actions may induce HDAC3 vii) TSP1/CD47 regulates effects of NO on the microvasculature339. |
| TSP-2 |
Expression: Highly expressed in pressure-overloaded hearts and in human patients with cardiac hypertrophy340. High circulating TSP-2 are associated with adverse outcome in HFpEF patients341. Role: Protects the pressure-overloaded heart from rupture340 and the aging heart from dilative cardiomyopathy146. Protective role in viral myocarditis through T reg-mediated anti-inflammatory actions342. Protects cardiomyocytes and preserves the integrity of the cardiac ECM in doxorubicin-induced cardiomyopathy343 |
No published data. | i) Inhibition of MMP synthesis and activity343. ii) Activation of Akt-mediated pro-survival pathways in cardiomyocytes343. |
| TSP-3 | Promotes cardiomyocyte injury in response to stress150 | Unknown | i) Induction of integrins in stressed cardiomyocytes through intracellular actions that promote sarcolemmal destabilization150 |
| TSP-4 |
Expression: Rapidly upregulated in the myocardium in response to angiotensin II-treatment, or TAC344. Role: Protects the pressure-overloaded heart from functional decompensation, systolic dysfunction and death, and restrains hypertrophy345. Transduces protective mechanosensitive signals requires for augmentation of contractility in response to an acute pressure load145 Has also been suggested to inhibit fibrosis in the pressure-overloaded heart140,346. |
Unknown. | i) Suppression of ECM protein synthesis in fibroblasts and endothelial cells140. ii) Activation of mechanosensitive Erk and Akt signaling in cardiomyocytes in response to stress145. iii) Intracellular actions, augmenting ER function and protecting from injury-related ER stress149,. |
| Tenascin-C |
Expression: Consistently upregulated and deposited in the cardiac interstitium in pressure-overloaded hearts142,143,83, and in myocarditis347. Upregulated in cardiomyocytes subjected to mechanical stress348. In human patients with DCM, increased serum levels of tenascin-C, and myocardial tenascin-C expression have been linked with adverse outcome349,350. Role: Has been suggested to accelerate fibrosis, hypertrophy and dysfunction of the pressure –overloaded heart142,351,143. However, in another study tenascin-C derived from bone marrow cells protected the pressure-overloaded heart from dysfunction and fibrosis by attenuating inflammation144. |
Expression: Highly expressed in the infarct border zone, and in remodeling myocardial areas in experimental models352 and in human patients with myocardial scars353 or ischemic cardiomyopathy212. In patients with ischemic cardiomyopathy interstitial activity evidenced by tenascin-C deposition predicted segmental recovery following revascularization212. Role: Has been suggested to accelerate adverse post-infarction remodeling by perturbing macrophage functions354 |
i) Activation of integrin-mediated secretion of fibrogenic cytokines in macrophages143. ii) Modulation of TLR responses in macrophages354. ii) Negative regulation of inflammation144. iii) Accentuation of fibroblast migration355 and fibroblast activation through TLR-dependent mechanisms356. iv) Modulation of adhesive interactions between the cardiomyocytes and the ECM352. |
| SPARC |
Expression: Increased levels of myocardial SPARC are noted in experimental models of pressure overload104, in aging hearts357,358. SPARC expression was associated with fibrosis in human cardiac allografts359. Role: Mediates collagen processing and fibrosis, and promotes diastolic dysfunction in models of pressure overload104. Has been suggested to protect against inflammation in viral inflammation360. |
Expression: Upregulated in experimental models of MI361,196 Role: Protects the infarcted heart from cardiac rupture and dysfunction by preserving the ECM network200 |
i) Contribution to post-synthetic pro-collagen processing104. ii) Activation of TGF-β signaling responses in cardiac fibroblasts200. |
| Osteopontin |
Expression: Marked myocardial upregulation of osteopontin is noted in experimental models of heart failure induced through pressure overload362, in volume overload363, in diabetic hearts364 and in hearts from mice with muscular dystrophy365. Myocardial osteopontin was increased in patients with end-stage dilated cardiomyopathy; levels were reduced upon unloading366. Highly expressed in the myocardium of patients with non-ischemic cardiomyopathy and associated with fibrotic lesions and hypertrophy367. In human patients with hypertension, osteopontin promoter variants that affect transcription were associated with diastolic function.368 Role: Suggested to mediate fibrosis, while preventing dilation in pressure-overloaded hearts and upon neurohumoral activation369,370,371,372. Pro-hypertrophic effects have been less consistently observed. In aging hearts, osteopontin derived from adipose tissue (and not from the myocardium) was suggested to promote cardiac fibrosis and dysfunction373. In a mouse model of Chagas disease, OPN was implicated in cardiac inflammation, fibrosis, and dysfunction374. OPN mediated fibrosis in a model of viral myocarditis375; however, in a model of autoimmune myocarditis, osteopontin did not affect inflammation376 |
Expression: Upregulated in myocardial infarcts and predominantly localized in activated macrophages377,378,379 Role: Protects the infarcted heart from ventricular dilation by promoting collagen deposition380 |
i) Stimulation of f fibroblast proliferation through integrin activation369,381, and protection of fibroblasts from apoptosis137. ii) Activation of pro-survival pathways in fibroblasts through miR-21139. iii) Stimulation of myofibroblast conversion382 iv) Activation of reparative and fibrogenic macrophages through galectin-3 upregulation 379,383 v) Activation of lymphocytes384. vi) Stimulation of cardiomyocyte apoptosis via CD44385 |
| Periostin |
Expression: Upregulated in activated myofibroblasts and deposited in the cardiac interstitium in models of cardiac pressure overload386,41,387,388. Increased myocardial expression in senescent mice389, in a model of volume overload390 and in models of cardiomyopathy induced through renal failure391. Negligible expression in a model of type II diabetes-related cardiomyopathy214. In human patients increased periostin expression in failing hearts was reduced upon unloading392 Role: Promotes hypertrophy and fibrosis in experimental models of pressure overload41. Promotes dysfunction in a model of hypertensive heart disease387 |
Expression: Markedly upregulated in infarct myofibroblasts and deposited in the ECM following infarction41,138,393 Role: Following non-reperfused infarction, periostin is essential for cardiac repair and protects from rupture, but mediates fibrosis and adverse remodeling41,138. Has been suggested to promote cardiac regeneration in neonatal394, and even in adult mice268. Regenerative effects in adult animals were not supported by studies using genetic manipulation strategies269 |
i) Activation and differentiation of cardiac fibroblasts, promoting migration and myofibroblast conversion138,395,396. ii) Regulation of collagen fibrillogenesis397. iii) Stimulation/activation of TGF-β signaling pathways398 iv) Modulation of MMP synthesis by many cell types, including interstitial cells and macrophages399. v) Stimulation of adult cardiomyocyte proliferation involving PI-3K activation has been reported268 |
Figure 3. Expression and actions of TSP-1 in failing hearts.
In a mouse model of cardiac pressure overload induced through transverse aortic constriction, TSP-1 immunoreactivity is localized predominantly in perivascular and interstitial areas (data from our published work136). TSP-1 overexpression in the pressure-overloaded heart may modulate inflammation, fibrosis and matrix metabolism through several distinct molecular pathways. First, TSP-1 plays an important role in TGF-β activation by binding to the Latency-associated peptide (LAP), thus triggering release of bioactive TGF-β. Second, TSP-1 may inhibit MMP activation, promoting matrix preservation. Third, TSP-1 may exert angiostatic actions. Fourth, TSP-1 may exert anti-inflammatory actions through effects on lymphocytes and macrophages. Fifth, TSP-1 may inhibit NO production and signaling.
Figure 4. Expression and function of the matricellular protein tenascin-C in the failing heart.
A-B: Tenascin-C immunoreactivity is localized in the interstitial and perivascular areas in a mouse model of cardiac pressure overload induced through transverse aortic constriction. Images from our own published work83. Tenascin-C may be produced by cardiomyocytes, myofibroblasts and leukocytes in response to mechanical stress or neurohumoral activation. When bound to the interstitial ECM, tenascin-C may exert fibrogenic actions by directly stimulating synthesis of ECM proteins by fibroblasts, or by activating macrophages through integrin or TLR-dependent mechanisms. Effects of tenascin-C on cardiomyocytes remain understudied.
The molecular targets of the matricellular proteins include a broad range of cytokines and growth factors, proteases, integrins and non-integrin cell surface receptors, such as CD44 and CD36. An additional layer of complexity in understanding the effects of the matricellular proteins was added by recently reported experimental findings suggesting important intracellular actions of the TSPs149,150. Considering the diverse functions of matricellular proteins, their multiple functional domains and their context-dependent effects, the relative contributions of specific actions in vivo remains poorly documented.
Proteoglycans
Proteoglycans are glycosylated proteins that consist of a core protein with one or more covalently attached glycosaminoglycan (GAG) chains. In the mammalian heart, the profile of ECM proteoglycan composition is dependent on topography. The pericellular matrix contains predominantly heparan sulfate proteoglycans (HSPGs), which are typically associated with the cell surface. In areas more distant from the surface of the cells, chondroitin- and dermatan sulfate-containing proteoglycans (CSPGs and DSPGs respectively) predominate151. In both human patients with heart failure and in animal models of myocardial disease, CSPGs accumulate in fibrotic regions152. The ECM in the pressure-overloaded heart is also enriched with a wide range of small leucine rich proteoglycans (SLRPs), such as biglycan, decorin, fibromodulin, lumican and osteoglycin. TGF-βs, angiotensin II, pro-inflammatory cytokines and mechanostransductive signaling markedly upregulate expression of SLRPs in cardiac fibroblasts153,154,155. Once secreted in the cardiac interstitium, SLRPs bind to collagen fibrils and organize the structural ECM, but may also interact with growth factors, and cell surface receptors to transduce or modulate signaling responses In vivo studies have implicated several SLRPs in regulation of cardiac fibrosis, remodeling and dysfunction following pressure overload123. In a model of transverse aortic constriction, biglycan was found to mediate fibrosis and cardiomyocyte hypertrophy in the pressure-overloaded myocardium156. Other SLRPs have been implicated in negative regulation of fibrotic and hypertrophic myocardial remodeling. In hypertensive rats, decorin gene therapy attenuated fibrosis and hypertrophy and improved function by inhibiting TGF−β -signaling157. Lumican has also been suggested to protect against systolic dysfunction in an isoproterenol infusion model, the cellular mechanism for the protective actions was not studied158. Osteoglycin protected the pressure-overloaded myocardium from diastolic dysfunction by attenuating inflammatory activation of macrophages and by inhibiting TGF-β-driven fibrogenic responses 159. The combined experience from various mouse models of cardiac remodeling suggests important roles for SLRPs in regulation of fibrosis and hypertrophy; however, their functional role is dependent on the pathophysiologic context, and the cellular targets and molecular interactors remain unknown. Moreover, proteomic studies in human hearts suggested that myocardial SLRP profiles may be dependent on topography, identifying atrial-specific processed forms of decorin that may be involved in atrial fibrillation160.
4.1.3. The role of ECM metabolism in regulation of geometry and function in the pressure-overloaded heart.
In both experimental models of left ventricular pressure overload and in human patients with long-standing untreated hypertension or aortic stenosis, early increases in myocardial stiffness occur in the absence of systolic dysfunction, and may be followed by late dilative remodeling and systolic functional depression. Although the basis for the transition likely involves several different cellular processes, changes in the composition of the ECM may be critical in regulation of cardiac geometry and function. Regulation of the balance between proteases and anti-proteases plays a crucial role in the biochemical profile of interstitial ECM proteins and has profound functional implications (Figure 5). Although only fibroblasts produce significant amounts of fibrillar collagens, the main structural components of the matrix, virtually all myocardial cell types (including cardiomyocytes, fibroblasts, immune cells and vascular cells) can produce and activate proteolytic enzymes that process ECM proteins161, thus altering the geometry and the mechanical properties of the myocardium. Cardiac pressure overload is associated with induction and activation of collagenases (such as MMP1, MMP8, and MMP13), gelatinases (such as MMP2 and MMP9), stromelysins/matrilysins and membrane-type MMPs162,163. TIMPs, are also upregulated in remodeling hearts and may exert matrix-preserving actions164,165. A large body of evidence suggests that MMP induction and activation may generate a predominantly proteolytic environment in the cardiac interstitium, leading to degradation of ECM proteins166. The relatively slow synthesis rate of collagen by cardiac fibroblasts is accelerated following pressure overload, but may not be sufficient to compensate for the pronounced matrix-degrading effects of MMPs167,168,10. Excessive degradation of endomysial collagen may precipitate systolic dysfunction in patients with hypertensive heart failure169. MMP induction may be mediated through activation of pro-inflammatory signaling pathways. For example, tumor necrosis factor (TNF)-α induces synthesis of a wide range of MMPs in both cardiomyocytes and fibroblasts and promotes dilation of the pressure-overloaded heart by degrading the supporting ECM170. The pro-inflammatory cytokine interleukin (IL)-1β also stimulates MMP expression in cardiac fibroblasts and may exert similar actions in vivo171,172. Development of systolic dysfunction in the presence of excessive MMP activation in the cardiac interstitium may involve several distinct mechanisms. First, because cardiomyocytes are dependent on interactions with a preserved matrix network, loss of survival signals transduced by intact ECM proteins may promote apoptosis and/or contractile dysfunction of cardiomyocytes under conditions of stress. Second, ECM fragments (matrikines) generated through protease activation may induce pro-inflammatory cascades30, or activate pro-apoptotic pathways in cardiomyocytes. Third, several members of the MMP family have been suggested to regulate signaling cascades through effects independent of ECM processing. MMPs can process CC and CXC chemokines 173,174 and cytokines (such as TNF−α)175, thus exerting context-dependent pro- or anti-inflammatory actions. Moreover, MMPs have been implicated in TGF-β activation176, and may cleave transmembrane receptors, such as integrins 177, or syndecans 178, thus modulating essential pro-inflammatory or fibrogenic cascades. MMPs may also act as intracellular mediators, promoting degradation of contractile proteins in cardiomyocytes, or modulating signal transduction responses in interstitial cells179,180,181. In contrast to the effects of MMP activation, overactive matrix-preserving mediators (such as induction of TIMPs) may promote deposition of structural ECM proteins, increasing myocardial stiffness and accentuating diastolic dysfunction182. It should be emphasized that, much like MMPs, TIMPs can also exert actions independent of MMP activity or ECM remodeling. For example, TIMP-1 has been suggested to promote cardiac fibrosis by facilitating a CD63/β1 integrin cascade that activates Smad-dependent signaling in cardiac fibroblasts165.
Figure 5. Sustained pressure overload triggers progressive left ventricular dilation and systolic dysfunction through changes in the protease/antiprotease balance.
In the early phase, mechanical stress induces a matrix-preserving fibroblast phenotype inducing collagen synthesis and production of antiproteases (such as TIMPs). Accentuated ECM deposition increases myocardial stiffness causing diastolic dysfunction. Prolonged pressure over load may be associated with transition of infiltrating fibroblasts to a matrix-degrading phenotype that produces matrix metalloproteinases (MMPs), thus causing ECM degradation and generating matrix fragments (matrikines). Matrikines may cause systolic dysfunction by promoting cardiomyocyte apoptosis and by inducing inflammation. Moreover, degradation of the ECM network may deprive cardiomyocytes from matrix-dependent signals required for preservation of function.
In addition to the established role of MMPs in myocardial ECM turnover, emerging evidence implicates two other families of proteases, the ADAM (A Disintegrin and Metalloproteinase), and the ADAMTS (ADAM with Thrombospondin Motifs)183,184. ADAM and ADAMTS family members can be activated in response to a wide range of stimuli and have multiple substrates. ADAMs mediate ectodomain shedding, the proteolytic cleavage of the extracellular domain of membrane bound molecules. ADAMTS members on the other hand, typically act as secreted proteases and have ECM protein substrates. In a model of left ventricular pressure overload, ADAM-17 expression in cardiomyocytes protected the heart from dilation, dysfunction and fibrosis through cleavage of β1 integrin185. ADAMTS2 on the other hand, was found to be upregulated in the pressure-overloaded myocardium and attenuated cardiac hypertrophy by inhibiting the PI3K/Akt axis186.
4.2. Effects of volume overload on the cardiac ECM
Despite its important role in heart failure associated with severe valvular regurgitant lesions, and its involvement in other cardiomyopathic conditions, volume overload remains a pathophysiologic and cell biological enigma. In contrast to the marked deposition of fibrillar collagens in the interstitium of pressure-overloaded hearts, volume overload is associated with loss of interstitial collagen, prominent ECM degradation, and induction of MMPs (Figure 6)187,188, 189. The cellular basis for the loss of collagen and the dominant activation of proteases in volume overload-induced cardiomyopathy remains unknown. Mechanical stretch in response to volume overload may affect gene expression in both interstitial cells and cardiomyocytes. Fibroblasts from volume overloaded hearts exhibited a “hypofibrotic phenotype”, characterized by reduced collagen and α-SMA synthesis190. It has been suggested that increased oxidative stress induced by mechanical stretch may activate an autophagic degradation of procollagen in volume overloaded hearts191. Effects of volume overload on macrophages and mast cells have also been implicated72,192. As important sources of MMPs and pro-inflammatory cytokines, mast cells and macrophages may promote degradation of the interstitial ECM, leading to dilative remodeling and systolic dysfunction. Although in vitro and in vivo studies have suggested that mechanical stretch in response to volume overload may promote cardiomyocyte apoptosis193 and alters the conformation of caveolae194, whether cardiomyocytes serve as important cellular effectors of ECM loss in volume-overloaded hearts has not been investigated.
Figure 6. The enigmatic basis of ECM degradation in the volume-overloaded heart.
Experimental evidence suggests that cardiac volume overload is associated with a matrix-degrading fibroblast phenotype and with high levels of interstitial MMPs. Immune cells (macrophages and mast cells) may contribute to the proteolytic environment by secreting MMPs. Persistent ECM degradation may trigger cardiomyocyte apoptosis and/or dysfunction and may be responsible for the dilation and systolic dysfunction typically observed in volume-overloaded hearts. The molecular links between mechanical stretch induced by volume overload and the selective activation of proteolytic pathways remain unknown.
4.3. The dynamic alterations of the cardiac ECM in the infarcted heart and in chronic ischemic cardiomyopathy
The adult mammalian heart has negligible regenerative capacity. Thus, following MI, the heart heals through activation of an inflammatory response that clears the wound from dead cardiomyocytes and activates reparative myofibroblasts, ultimately leading to formation of a scar, predominantly comprised of cross-linked collagen. Repair of the infarcted myocardium can be divided into three distinct but overlapping phases: the inflammatory phase, the proliferative phase and the maturation phase20. Dynamic changes in the biochemical profile and composition of the ECM play a critical role in regulation of key cellular events in all three phases of infarct healing195,133. During the inflammatory phase, early degradation of the ECM generates matrikines that may serve as danger signals contributing to activation of an inflammatory and reparative program. Moreover, formation of a provisional fibrin-based matrix network derived from extravasated fibrinogen and plasma fibronectin196 serves as a highly plastic conduit for infiltrating inflammatory cells. As macrophages clear the infarct from dead cells and matrix debris, induction of anti-inflammatory mediators suppresses inflammation and marks the transition to the proliferative phase. At this stage, activated myofibroblasts deposit both structural and matricellular ECM proteins197, preserving the structural integrity of the ventricle. Finally, during the maturation phase, the collagenous ECM is crosslinked and the fibroblasts become quiescent198, and may undergo apoptosis. The matrix-dependent molecular steps that regulate the reparative response following MI are critical for protection of the infarcted heart from cardiac rupture and from the pathogenesis of heart failure. Moreover, a large body of evidence suggests that disruption of matricellular genes exclusively or predominantly induced in the infarct zone, has a major impact on the extent of adverse post-infarction remodeling199,200,201. These observations suggest that the characteristics and biochemical composition of the scar are a major determinant of cardiac remodeling following MI and that dysregulation of ECM-dependent responses in the healing infarct may drive post-infarction heart failure. The role of the ECM network in post-infarction cardiac remodeling has been recently reviewed133.
As the infarct heals, the viable non-infarcted myocardium remodels, exhibiting cardiomyocyte hypertrophy, accompanied by progressive interstitial fibrosis. Thus, although endogenous anti-inflammatory signals suppress inflammation in the infarct zone, in the viable non-infarcted segments, increased wall stress may locally activate cardiomyocytes, macrophages, and fibroblasts, triggering chronic remodeling of the ECM network202,203. Studies in human patients surviving acute MI suggest that high circulating levels of MMPs may predict adverse dilative remodeling, systolic dysfunction and progression to heart failure204,205. Although it is tempting to hypothesize that accentuated and accelerated chamber dilation in a subset of MI patients may be caused by overactive matrix-degrading pathways, the contribution of chronic ECM remodeling in non-infarcted segments to adverse remodeling and development of post-infarction heart failure remains poorly documented. Understanding the functional consequences of specific cellular events in remote viable myocardial segments is particularly challenging, considering that traditional loss- or gain-of-function interventions also target cells in the infarct and in the border zone that may affect cardiac hemodynamics, thus indirectly modulating responses in the non-infarcted myocardium.
Alterations in the ECM network may also contribute to the pathogenesis of chronic ischemic cardiomyopathy, in the absence of MI. Unfortunately, the effects of low flow ischemia or brief ischemic insults on the myocardial ECM remain underexplored and poorly understood. In a porcine model, reduction of coronary flow to 50% of the baseline for 90 min was sufficient to activate MMP9 without affecting collagenase levels, or have effects on the structure of the cardiac ECM206. Moreover, in a mouse model of brief repetitive myocardial ischemia and reperfusion, deposition of the matricellular protein tenascin-C accompanied interstitial fibrosis, in the absence of a completed infarction207. These findings suggest that ischemic events of low duration or intensity may trigger remodeling of the cardiac ECM without causing lethal cardiomyocyte injury. Oxidative stress, triggered by ischemia/reperfusion may be responsible for the ECM changes. The clinical relevance of these observations in ischemic cardiomyopathy is supported by studies in human patients. MMP2 and MMP9 activation was noted following reperfusion after cardioplegia in myocardial samples from patients undergoing aortocoronary bypass208. Moreover, patients with ischemic cardiomyopathy exhibited increased myocardial MMP9 expression and activity, and high MMP14 levels209,210; increased MMP expression was reversed following unloading through left ventricular assist device implantation211. Recovery of function following revascularization in ischemic cardiomyopathy may also involve the cardiac ECM. In patients undergoing aortocoronary bypass surgery for chronic ischemic cardiomyopathy, segments with functional recovery had higher levels of tenascin-C, associated with a more cellular intesrtitium212. In contrast, myocardial segments exhibiting reduced interstitial activity, evidenced by lower levels of matricellular proteins, reduced numbers of inflammatory leukocytes and more mature collagen, did not recover function following revascularization212,213. Thus, an active, highly cellular interstitial environment, enriched in matricellular proteins and capable of transducing growth factor responses may be required for structural and functional recovery of chronically ischemic fibrotic myocardial segments.
4.4. The ECM in diabetes-associated heart failure
Diabetes, obesity and metabolic dysfunction are associated with progressive expansion of the interstitial or perivascular ECM in experimental animal models214 and in human patients215. The cellular basis of diabetes-associated fibrosis remains poorly understood216, as studies exploring cell-specific actions in vivo are lacking. Oxidative stress, generation of advanced glycation end-products (AGEs), neurohumoral activation, endothelin-1 induction, adipokine secretion, and stimulation of pro-inflammatory cascades in response to metabolic dysregulation may directly activate cardiac fibroblasts, promoting a matrix-synthetic phenotype. Induction of matricellular proteins, such as TSP-1, is prominent in diabetic hearts217,218 and may contribute to activation of TGF-β signaling, directly activating cardiac fibroblasts. Despite evidence suggesting local TGF-β activation219, diabetes-associated cardiac fibrosis may not involve myofibroblast conversion214. Macrophages, cardiomyocytes, vascular endothelial cells and pericytes may also acquire a fibrogenic program, secreting growth factors and stimulating fibroblast-derived ECM synthesis. AGE-induced crosslinking of the collagenous ECM in vessels and myocardium, may reduce vascular compliance and increase myocardial stiffness220.
In human patients, obesity, diabetes and metabolic dysfunction markedly increase the risk of HFpEF, independently of the coronary artery disease221,222. Clinical studies have identified a distinct obesity-related phenotype of human HFpEF223, associated with increased plasma volume, more severe concentric left ventricular hypertrophy and greater right ventricular dilatation, despite lower plasma levels of natriuretic peptides223,224. Microvascular inflammation in obese diabetic subjects may stimulate fibrogenic signaling26,225, promoting ECM expansion and collagen crosslinking, and significantly contributing to diastolic dysfunction26. Considering the perturbations in cardiomyocyte and vascular cell phenotype and function typically associated with diabetes226,227, to what extent fibrogenic actions and ECM remodeling contribute to diastolic dysfunction and adverse outcome in diabetic patients remains unclear.
4.5. The ECM in age-associated cardiac dysfunction
Studies in both human subjects and animal models have consistently documented perivascular and interstitial accumulation of collagen in senescent hearts228,229;230. Some studies have suggested that age-associated fibrosis may reflect attenuation of matrix degradation due to a reduction in MMP synthesis, rather than accentuated collagen transcription231,232, 233, 234. Increased collagen crosslinking may also contribute to fibrosis in aging hearts, by reducing the susceptibility of the interstitial ECM to protease-mediated degradation235.
Aging-associated fibrosis may have important functional consequences. Aging is typically associated with a decline in diastolic function and reduced exercise capacity in the absence of significant effects on systolic function at rest. Deposition of cross-linked collagen fibers may reduce myocardial compliance, contributing to the pathogenesis of HFpEF in elderly subjects. However, because aging also affects cardiomyocyte relaxation properties, the relative contribution of interstitial ECM changes in the pathogenesis of senescence-associated diastolic dysfunction remains poorly documented. Myocardial deposition of ECM proteins may also account for the increased prevalence of conduction defects and arrhythmic events in older patients.
The mechanisms responsible for aging-associated cardiac fibrosis remain poorly understood. Activation of neurohumoral pathways, chronic low level induction of pro-inflammatory mediators, activation of TGF-βs and other fibrogenic mediators, ROS generation, and downmodulation of protective anti-fibrotic signals have been implicated in activation of a fibrotic response in the aging heart236. However, the fundamental link between aging and activation of a fibrogenic program remains unclear, and most of the evidence implicating specific mediators is associative.
4.6. The ECM in genetic cardiomyopathies
Monogenic cardiomyopathies caused by single pathogenetic mutations account for a relatively small proportion of heart failure patients237. It is unclear whether certain mutations can cause heart failure through primary activation of a fibrogenic program in cardiac interstitial cells. In postmortem autopsies of young patients dying from sudden cardiac death, primary cardiac fibrosis (defined as myocardial fibrosis in the absence of identifiable causes, or known cardiomyocyte pathology) is commonly found238. However, in many of these cases, genetic analysis identified cardiomyocyte-specific gene mutations239, suggesting that fibrosis may not be triggered through primary activation of interstitial cells, but may reflect activation through cardiomyocyte-derived fibrogenic signals. In a recent study, subjects with a frameshift mutation of SEPRINE1, the gene encoding PAI-1, exhibited primary cardiac fibrosis, attributed to the release of cardiomyocyte-derived TGF-β240. In the much more common genetic conditions associated with dilated cardiomyopathy (DCM)241 or hypertrophic cardiomyopathy (HCM)242,243, interstitial fibrotic changes have been extensively documented, and are associated with worse prognosis243. Transgenic mice recapitulating the human disease also exhibit substantial interstitial fibrosis244,245. In most monogenic cardiomyopathies, heart failure is due to primary alterations in myofilament function. Traditional concepts have suggested that interstitial cell activation and ECM perturbations may simply represent an epiphenomenon, reflecting increased hemodynamic loads, or responses to primary cardiomyocyte injury. However, recent evidence from mouse models of genetic cardiomyopathies has challenged the notion that ECM remodeling is an innocent companion. In transgenic mouse models of HCM, myofibroblast-specific disruption or pharmacologic inhibition of TGF-β signaling reduced myocardial fibrosis, prolonged survival, and preserved cardiac function246,247. These observations may suggest that activation of a fibrogenic program may exacerbate dysfunction and worsen outcome in subjects with sarcomeric mutations.
Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) develop arrhythmias, associated with expansion and activation of fibroadipocyte populations, ECM deposition and fatty infiltration248,249,250,251,33. Experimental evidence suggests that in subsets of ARVC patients, fibrofatty infiltration may be triggered by primary phenotypic alterations of interstitial cells. Genetic analysis has identified mutations in genes encoding desmosome proteins (including plakophilin-2, desmoplakin and desmoglein-2) in many ARVC patients252,253,254. In mice, loss of desmoplakin in a subset of fibroadipocyte-like interstitial cells triggered adipocyte through modulation of Wnt-dependent signaling255,256. To what extent these cells act by remodeling the cardiac ECM is unknown. In other cases, fibrosis may reflect activation of a fibrogenic program in cardiomyocytes257. Thus, the cellular basis of ECM remodeling in ARVC remains unclear.
5. ECM modulation in heart failure therapeutics
Because of its important role in preserving cardiac geometry and function, its ubiquitous presence in the microenvironment of all cell types, and its crucial involvement in regulation of cellular responses in myocardial remodeling, the ECM is an attractive therapeutic target in heart failure. In fact, some of the established therapeutic approaches for heart failure patients may act, at least in part by targeting the ECM. ACE inhibition, AT1R blockade, β-adrenergic receptor antagonism, and mechanical unloading modulate deposition and metabolism of the ECM in human patients with heart failure258,211. Whether the effects of these interventions on the ECM are causally implicated in mediating their protective actions remains unknown. Emerging concepts suggest that targeting the cardiac ECM may hold promise to prevent adverse remodeling in both ischemic and non-ischemic cardiomyopathy, and to attenuate diastolic dysfunction in HFpEF patients. Moreover, some experimental studies have suggested that the cardiac ECM may hold the key to the visionary goal of myocardial regeneration.
5.1. ECM modulation to preserve geometry and function of the failing infarcted heart.
In the remodeling infarcted heart, tight regulation of ECM deposition and cross-linking may protect from dilative remodeling and from the development of heart failure, while preventing overactive fibrosis and diastolic dysfunction. Experimental evidence suggests that an optimal balance of matrix-synthetic and matrix-degrading pathways is needed. Excessive accumulation of cross-linked collagenous ECM increases myocardial stiffness and promotes diastolic dysfunction. On the other hand, overactivation of MMP-driven proteolysis may promote dilative remodeling, causing systolic dysfunction. The major therapeutic challenge for implementation is to achieve the optimal balance of matrix metabolism for every patient at risk for post-infarction heart failure. Considering the pathophysiological heterogeneity of post-infarction remodeling, use of biomarkers and imaging strategies to measure ECM composition and metabolism is needed in order to stratify the patients259 and to identify candidates for specific interventions. Individuals with overactive pro-fibrotic responses may benefit from anti-fibrotic strategies targeting ECM deposition or crosslinking. On the other hand, other patients may exhibit a predominant proteolytic environment in the infarcted heart and may require strategies that restore the ECM network increasing tensile strength of the infarct. Findings suggesting age-associated defects in growth factor responses and in ECM deposition following MI260 may suggest that in the elderly, measures to improve the reparative reserve may be more appropriate.
5.2. Targeting the cardiac ECM in HFpEF
The association between collagen deposition and myocardial stiffness in HFpEF patients is well-established261. Although inhibition of cardiac fibrosis seems an attractive therapeutic approach for HFpEF patients, implementation is hampered by several concerns. First, in contrast to fibrotic conditions in other systems (such as idiopathic pulmonary fibrosis or scleroderma), cardiac fibrosis is not a primary pathologic condition and often reflects activation of a reparative program in an organ that lacks effective regenerative capacity. It is difficult to establish a causative relation between ECM deposition and adverse outcome in human patients with HFpEF. Although fibrosis changes in HFpEF has clear and consistent adverse prognostic implications, these associations may represent an epiphenomenon, reflecting worse outcome in subjects with worse primary cardiomyocyte injury. Interstitial cells are heterogeneous and have a wide range of functions. The reparative actions of cardiac myofibroblasts are obvious in MI60; however, even in models of non-infarctive cardiac fibrosis that may recapitulate some features of human HFpEF, protective actions of cardiac myofibroblasts have been demonstrated30. Second, human HFpEF is pathophysiologically heterogeneous. Extensive biomarker-driven stratification may be required to identify subjects exhibiting overactive fibrotic responses that may be responsible for dysfunction and heart failure262. Third, the reparative functions of fibroblasts and the need to preserve and repair injury-related perturbations of the ECM network may limit chronic implementation of anti-fibrotic strategies. Even if patient subsets with inappropriate chronic myocardial ECM deposition are identified, the need for continuous administration of agents that attenuate fibroblast activation may carry significant risks, by abrogating essential reparative responses. Ultimately, success or failure of anti-fibrotic strategies in the heart will need to be tested in carefully-designed clinical investigations
5.3. Matricellular targets in failing hearts
The biology of the matricellular proteins may suggest attractive strategies to modulate adverse remodeling in failing hearts. Experimental studies have demonstrated that members of the matricellular family (such as TSP-1, and SPARC) may protect the failing heart from adverse remodeling and dysfunction122,199,136,200. Matricellular proteins are multidomain molecules that regulate cellular responses through outside-in signaling. Thus, identification of specific domains responsible for the protective effects of matricellular proteins could lead to development of peptide-based approaches that reproduce these effects and localize protective signaling in the area of interest. Unfortunately, therapeutic implementation of such approaches is hampered by the daunting complexity and contextual actions of matricellular proteins that may be dependent on the profile of the interstitial cellular infiltrate, the composition of the ECM and the cytokine and growth factor milieu.
5.4. Can manipulation of the ECM promote cardiac regeneration?
Despite intriguing early findings, regeneration of the adult heart remains an unfulfilled promise. In vitro studies, the role of the ECM in embryonic cardiac development, and in vivo experiments in amphibian or fish models and in neonatal mice suggest that the composition of the ECM may play a critical role in activation of a regenerative program in the myocardium. First, in vitro, ECM composition profoundly affects cell cycle entry in cardiomyocyte progenitors and in neonatal cardiomyocytes263,264. Second, in zebrafish, genetic ablation of matrix-producing fibroblasts or fibronectin loss impaired the myocardial regenerative response265,266. Clearly, gaining translationally-relevant insights from fish models is a major challenge. Despite the abundant presence of myofibroblasts and high expression of fibronectin mammalian infarcts do not remuscularize, suggesting that ECM- and fibroblast-dependent actions may not be sufficient to activate a regenerative program. Third, some experimental studies in mammals have suggested that matricellular macromolecules may trigger proliferation of neonatal and even adult cardiomyocytes. Agrin, a large extracellular heparan sulfate proteoglycan, has been suggested to serve as an essential component of the regenerative neonatal ECM, promoting cardiomyocyte cell cycle re-entry in both neonatal and adult mice267. Moreover, periostin triggered cell cycle re-entry in differentiated adult cardiomyocytes in an integrin-dependent manner, and when administered as an epicardial gelfoam patch following infarction, improved cardiac function and attenuated cardiac remodeling268. Considering known biology on the challenges and complexities of myocardial regeneration, the notion that a single matrix macromolecule can remuscularize the adult mammalian heart is not plausible. For example, the idea that periostin can regenerate the heart is challenged by the abundance of periostin in the infarcted mouse myocardium in the absence of regeneration, and by the lack of regenerative capacity in infarcted periostin-overexpressing mice269. Despite some promising findings, whether modulation of the ECM profile in failing hearts could be used to facilitate activation of a regenerative program in remains unknown. Clearly, any attempt to remuscularize the heart would require a matrix environment that supports proliferating cardiomyocytes, or cardiomyocyte progenitors, and promotes syncytial function. Studies demonstrating the role of Yes-associated protein (YAP) signaling in neonatal heart regeneration highlight the requirement for molecular links between the ECM and the cardiac cytoskeleton270,271. However, a “regenerative” ECM profile is unlikely to be sufficient to trigger formation of new myocardium, a process that may also require activation of an endogenous regenerative program by cardiomyocytes and vascular cells.
5.5. Matrix-driven strategies to engineer a bioartificial heart
Recent technological advances in perfusion-decellularization strategies have generated decellularized cardiac matrices that may serve as scaffold to engineer cardiac grafts272,273,274. Subsequently the matrices can be repopulated with induced pluripotent stem cell-derived cardiomyocytes in order to generate structures resembling human myocardium. This technology is at an early stage. Although tissue constructs with definitive sarcomeric structure, contractile function and electrical conduction have been generated275, several major challenges remain that currently preclude clinical translation. Coagulation dysfunction due to incomplete re-endothelialization and subsequent activation of the coagulation system, the absence of functional valvular structures, the lack of a conduction system for transmission of electrical activity, and the potential for immunogenicity and inflammatory activation are major limiting factors of this intriguing strategy. Despite these challenging problems, this approach may represent the first step towards the generation of functional bioartificial cardiac grafts.
6. Conclusions:
The myocardial ECM network contributes to cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission and by transducing molecular signals that regulate cell phenotype and function. In failing hearts, expansion of the cardiac interstitium, induction of both structural and matricellular ECM proteins, generation of bioactive matrix fragments, and alterations in matrix biochemistry may play a critical role in regulating inflammatory, reparative, fibrotic, angiogenic, and even regenerative responses. Thus, the cardiac ECM is a key regulator of cardiac remodeling both through effects of its structural constituents on the mechanical properties of the heart and through regulation of cellular responses. Dissecting the mechanistic contributions of ECM macromolecules in cardiac remodeling is critical for understanding the pathogenetic basis of heart failure in both ischemic and non-ischemic cardiomyopathy. Moreover, systematic characterization of the biochemical profile of ECM proteins in patients with myocardial disease is needed, in order to identify perturbations associated with human heart failure.
Acknowledgments
SOURCES OF FUNDING: Dr Frangogiannis’ laboratory is supported by NIH grants R01 HL76246 and R01 HL85440 and by grants PR151029 and PR151134 from the Department of Defense Congressionally Directed Medical Research Programs (CDMRP). The schematic cartoons were designed using Servier Medical Art (https:smart.servier.com).
NON-STANDARD ABBREVIATIONS:
- α-SMA
α-smooth muscle actin
- ACE
angiotensin converting enzyme
- ADAM
A disintegrin and metalloproteinase
- ADAMTS
A disintegrin and metalloproteinase with thrombospondin motifs
- AGEs
advanced glycation end-products
- ARVC
arrhythmogenic right ventricular cardiomyopathy
- AT1R
angiotensin II type 1 receptor
- AT2R
angiotensin II type 2 receptor
- BMP
bone morphogenetic protein
- CAMKII
Ca2+/calmodulin-dependent protein kinase II
- CSPGs
chondroitin sulfate proteoglycans
- DCM
dilated cardiomyopathy
- DSPGs
dermatan sulfate proteoglycans
- ECM
extracellular matrix
- ED-A
extra domain A
- EndMT
endothelial to mesenchymal transition
- ET-1
endothelin-1
- FAK
focal adhesion kinase
- FGF
fibroblast growth factor
- Fn
fibronectin
- GAG
glycosaminoglycan
- HCM
hypertrophic cardiomyopathy
- HFpEF
heart failure with preserved ejection fraction
- HFrEF
heart failure with reduced ejection fraction
- HSPGs
heparin sulfate proteoglycans
- IL
interleukin
- LOX
lysyl oxidase
- LTBP
latent TGF-β-binding protein
- MAPK
mitogen-activated protein kinase
- MI
myocardial infarction
- MMP
matrix metalloproteinase
- MRTF
myocardin-related transcription factor
- PAI-1
plasminogen activator inhibitor-1
- PCOLCE2
procollagen C-endopeptidase enhancer 2
- RAAS
renin-angiotensin-adlosterone system
- RhoA
Ras homolog gene family, member A
- ROCK
Rho-associated protein kinase
- ROS
reactive oxygen species
- SLRPs
small leucine rich proteoglycans
- SPARC
secreted protein acidic and rich in cysteine
- TG
transglutaminase
- TGF
transforming growth factor
- TIMP
tissue inhibitor of metalloproteinases
- TNF
tumor necrosis factor
- TRPV4
Transient receptor potential cation channel subfamily V member 4
- TSP
thrombospondin
- YAP
Yes-associated protein
Footnotes
DISCLOSURES: None
REFERENCES:
- 1.Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 2014; 15:786–801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hynes RO. The extracellular matrix: not just pretty fibrils. Science 2009; 326:1216–1219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev 2016; 97:4–27. [DOI] [PubMed] [Google Scholar]
- 4.Yang H, Borg TK, Wang Z, Ma Z, Gao BZ. Role of the basement membrane in regulation of cardiac electrical properties. Ann Biomed Eng 2014; 42:1148–1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Medugorac I, Jacob R. Characterisation of left ventricular collagen in the rat. Cardiovasc Res 1983; 17:15–21. [DOI] [PubMed] [Google Scholar]
- 6.Leonard BL, Smaill BH, LeGrice IJ. Structural remodeling and mechanical function in heart failure. Microsc Microanal 2012; 18:50–67. [DOI] [PubMed] [Google Scholar]
- 7.Borg TK, Caulfield JB. The collagen matrix of the heart. Fed Proc 1981; 40:2037–2041. [PubMed] [Google Scholar]
- 8.Bashey RI, Martinez-Hernandez A, Jimenez SA. Isolation, characterization, and localization of cardiac collagen type VI. Associations with other extracellular matrix components. Circ Res 1992; 70:1006–1017. [DOI] [PubMed] [Google Scholar]
- 9.Bishop JE, Laurent GJ. Collagen turnover and its regulation in the normal and hypertrophying heart. Eur Heart J 1995; 16 Suppl C:38–44. [DOI] [PubMed] [Google Scholar]
- 10.Jugdutt BI. Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 2003; 108:1395–1403. [DOI] [PubMed] [Google Scholar]
- 11.Weber KT. Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol 1989; 13:1637–1652. [DOI] [PubMed] [Google Scholar]
- 12.Barallobre-Barreiro J, Lynch M, Yin X, Mayr M. Systems Biology - Opportunities and Challenges: The Application of Proteomics to Study the Cardiovascular Extracellular Matrix. Cardiovasc Res 2016. [DOI] [PMC free article] [PubMed]
- 13.Krasny L, Paul A, Wai P, Howard BA, Natrajan RC, Huang PH. Comparative proteomic assessment of matrisome enrichment methodologies. Biochem J 2016; 473:3979–3995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.de Castro Bras LE, Ramirez TA, DeLeon-Pennell KY, Chiao YA, Ma Y, Dai Q, Halade GV, Hakala K, Weintraub ST, Lindsey ML. Texas 3-step decellularization protocol: looking at the cardiac extracellular matrix. J Proteomics 2013; 86:43–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Barallobre-Barreiro J, Didangelos A, Schoendube FA, Drozdov I, Yin X, Fernandez-Caggiano M, Willeit P, Puntmann VO, Aldama-Lopez G, Shah AM, Domenech N, Mayr M. Proteomics analysis of cardiac extracellular matrix remodeling in a porcine model of ischemia/reperfusion injury. Circulation 2012; 125:789–802. [DOI] [PubMed] [Google Scholar]
- 16.Lapidos KA, Kakkar R, McNally EM. The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. Circ Res 2004; 94:1023–1031. [DOI] [PubMed] [Google Scholar]
- 17.Michele DE, Kabaeva Z, Davis SL, Weiss RM, Campbell KP. Dystroglycan matrix receptor function in cardiac myocytes is important for limiting activity-induced myocardial damage. Circ Res 2009; 105:984–993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Michel JB. Anoikis in the cardiovascular system: known and unknown extracellular mediators. Arterioscler Thromb Vasc Biol 2003; 23:2146–2154. [DOI] [PubMed] [Google Scholar]
- 19.Frangogiannis NG. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med 2018. [DOI] [PubMed]
- 20.Frangogiannis NG. Pathophysiology of Myocardial Infarction. Compr Physiol 2015; 5:1841–1875. [DOI] [PubMed] [Google Scholar]
- 21.Dai Z, Aoki T, Fukumoto Y, Shimokawa H. Coronary perivascular fibrosis is associated with impairment of coronary blood flow in patients with non-ischemic heart failure. J Cardiol 2012; 60:416–421. [DOI] [PubMed] [Google Scholar]
- 22.Varagic J, Frohlich ED, Diez J, Susic D, Ahn J, Gonzalez A, Lopez B. Myocardial fibrosis, impaired coronary hemodynamics, and biventricular dysfunction in salt-loaded SHR. Am J Physiol Heart Circ Physiol 2006; 290:H1503–1509. [DOI] [PubMed] [Google Scholar]
- 23.Ytrehus K, Hulot JS, Perrino C, Schiattarella GG, Madonna R. Perivascular fibrosis and the microvasculature of the heart. Still hidden secrets of pathophysiology? Vascul Pharmacol 2018. [DOI] [PubMed]
- 24.Aoki T, Fukumoto Y, Sugimura K, Oikawa M, Satoh K, Nakano M, Nakayama M, Shimokawa H. Prognostic impact of myocardial interstitial fibrosis in non-ischemic heart failure. -Comparison between preserved and reduced ejection fraction heart failure. Circ J 2011; 75:2605–2613. [DOI] [PubMed] [Google Scholar]
- 25.Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 2015; 131:550–559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62:263–271. [DOI] [PubMed] [Google Scholar]
- 27.Kato S, Saito N, Kirigaya H, Gyotoku D, Iinuma N, Kusakawa Y, Iguchi K, Nakachi T, Fukui K, Futaki M, Iwasawa T, Taguri M, Kimura K, Umemura S. Prognostic significance of quantitative assessment of focal myocardial fibrosis in patients with heart failure with preserved ejection fraction. Int J Cardiol 2015; 191:314–319. [DOI] [PubMed] [Google Scholar]
- 28.Iwanaga Y, Aoyama T, Kihara Y, Onozawa Y, Yoneda T, Sasayama S. Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. J Am Coll Cardiol 2002; 39:1384–1391. [DOI] [PubMed] [Google Scholar]
- 29.Wang J, Hoshijima M, Lam J, Zhou Z, Jokiel A, Dalton ND, Hultenby K, Ruiz-Lozano P, Ross J Jr., Tryggvason K, Chien KR. Cardiomyopathy associated with microcirculation dysfunction in laminin alpha4 chain-deficient mice. J Biol Chem 2006; 281:213–220. [DOI] [PubMed] [Google Scholar]
- 30.Russo I, Cavalera M, Huang S, Su Y, Hanna A, Chen B, Shinde AV, Conway SJ, Graff J, Frangogiannis NG. Protective Effects of Activated Myofibroblasts in the Pressure-Overloaded Myocardium Are Mediated Through Smad-Dependent Activation of a Matrix-Preserving Program. Circ Res 2019; 124:1214–1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Khan R, Sheppard R. Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology 2006; 118:10–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Rubart M, Tao W, Lu XL, Conway SJ, Reuter SP, Lin SF, Soonpaa MH. Electrical coupling between ventricular myocytes and myofibroblasts in the infarcted mouse heart. Cardiovasc Res 2018; 114:389–400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Frangogiannis NG. Fibroblasts and the extracellular matrix in right ventricular disease. Cardiovasc Res 2017; 113:1453–1464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Nattel S Molecular and Cellular Mechanisms of Atrial Fibrosis in Atrial Fibrillation. JACC Clin Electrophysiol 2017; 3:425–435. [DOI] [PubMed] [Google Scholar]
- 35.Messerli FH, Rimoldi SF, Bangalore S. The Transition From Hypertension to Heart Failure: Contemporary Update. JACC Heart Fail 2017; 5:543–551. [DOI] [PubMed] [Google Scholar]
- 36.Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA 1996; 275:1557–1562. [PubMed] [Google Scholar]
- 37.Sasayama S, Ross J Jr., Franklin D, Bloor CM, Bishop S, Dilley RB. Adaptations of the left ventricle to chronic pressure overload. Circ Res 1976; 38:172–178. [DOI] [PubMed] [Google Scholar]
- 38.Leslie KO, Taatjes DJ, Schwarz J, vonTurkovich M, Low RB. Cardiac myofibroblasts express alpha smooth muscle actin during right ventricular pressure overload in the rabbit. Am J Pathol 1991; 139:207–216. [PMC free article] [PubMed] [Google Scholar]
- 39.Wang J, Chen H, Seth A, McCulloch CA. Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 2003; 285:H1871–1881. [DOI] [PubMed] [Google Scholar]
- 40.Shiojima I, Aikawa M, Suzuki J, Yazaki Y, Nagai R. Embryonic smooth muscle myosin heavy chain SMemb is expressed in pressure-overloaded cardiac fibroblasts. Jpn Heart J 1999; 40:803–818. [DOI] [PubMed] [Google Scholar]
- 41.Oka T, Xu J, Kaiser RA, Melendez J, Hambleton M, Sargent MA, Lorts A, Brunskill EW, Dorn GW 2nd, Conway SJ, Aronow BJ, Robbins J, Molkentin JD. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ Res 2007; 101:313–321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 2007; 13:952–961. [DOI] [PubMed] [Google Scholar]
- 43.Moore-Morris T, Guimaraes-Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A, Stallcup WB, Gu Y, Dalton ND, Cedenilla M, Gomez-Amaro R, Zhou B, Brenner DA, Peterson KL, Chen J, Evans SM. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Invest 2014; 124:2921–2934. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Ali SR, Ranjbarvaziri S, Talkhabi M, Zhao P, Subat A, Hojjat A, Kamran P, Muller AM, Volz KS, Tang Z, Red-Horse K, Ardehali R. Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ Res 2014; 115:625–635. [DOI] [PubMed] [Google Scholar]
- 45.van Putten S, Shafieyan Y, Hinz B. Mechanical control of cardiac myofibroblasts. J Mol Cell Cardiol 2016; 93:133–142. [DOI] [PubMed] [Google Scholar]
- 46.Ross RS, Borg TK. Integrins and the myocardium. Circ Res 2001; 88:1112–1119. [DOI] [PubMed] [Google Scholar]
- 47.Perrucci GL, Barbagallo VA, Corliano M, Tosi D, Santoro R, Nigro P, Poggio P, Bulfamante G, Lombardi F, Pompilio G. Integrin alphanubeta5 in vitro inhibition limits pro-fibrotic response in cardiac fibroblasts of spontaneously hypertensive rats. J Transl Med 2018; 16:352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Perrucci GL, Rurali E, Pompilio G. Cardiac fibrosis in regenerative medicine: destroy to rebuild. J Thorac Dis 2018; 10:S2376–S2389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Herum KM, Lunde IG, Skrbic B, Florholmen G, Behmen D, Sjaastad I, Carlson CR, Gomez MF, Christensen G. Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress. J Mol Cell Cardiol 2013; 54:73–81. [DOI] [PubMed] [Google Scholar]
- 50.Follonier Castella L, Gabbiani G, McCulloch CA, Hinz B. Regulation of myofibroblast activities: calcium pulls some strings behind the scene. Exp Cell Res 2010; 316:2390–2401. [DOI] [PubMed] [Google Scholar]
- 51.Rahaman SO, Grove LM, Paruchuri S, Southern BD, Abraham S, Niese KA, Scheraga RG, Ghosh S, Thodeti CK, Zhang DX, Moran MM, Schilling WP, Tschumperlin DJ, Olman MA. TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice. J Clin Invest 2014; 124:5225–5238. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Li Q, Xu Y, Li X, Guo Y, Liu G. Inhibition of Rho-kinase ameliorates myocardial remodeling and fibrosis in pressure overload and myocardial infarction: role of TGF-beta1-TAK1. Toxicol Lett 2012; 211:91–97. [DOI] [PubMed] [Google Scholar]
- 53.Zhou Y, Huang X, Hecker L, Kurundkar D, Kurundkar A, Liu H, Jin TH, Desai L, Bernard K, Thannickal VJ. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest 2013; 123:1096–1108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Clemente CF, Tornatore TF, Theizen TH, Deckmann AC, Pereira TC, Lopes-Cendes I, Souza JR, Franchini KG. Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice. Circ Res 2007; 101:1339–1348. [DOI] [PubMed] [Google Scholar]
- 55.Liu S, Xu SW, Kennedy L, Pala D, Chen Y, Eastwood M, Carter DE, Black CM, Abraham DJ, Leask A. FAK is required for TGFbeta-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype. Mol Biol Cell 2007; 18:2169–2178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Kennedy L, Shi-Wen X, Carter DE, Abraham DJ, Leask A. Fibroblast adhesion results in the induction of a matrix remodeling gene expression program. Matrix Biol 2008; 27:274–281. [DOI] [PubMed] [Google Scholar]
- 57.Lighthouse JK, Small EM. Transcriptional control of cardiac fibroblast plasticity. J Mol Cell Cardiol 2016; 91:52–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Zhao XH, Laschinger C, Arora P, Szaszi K, Kapus A, McCulloch CA. Force activates smooth muscle alpha-actin promoter activity through the Rho signaling pathway. J Cell Sci 2007; 120:1801–1809. [DOI] [PubMed] [Google Scholar]
- 59.Sarrazy V, Koehler A, Chow ML, Zimina E, Li CX, Kato H, Caldarone CA, Hinz B. Integrins alphavbeta5 and alphavbeta3 promote latent TGF-beta1 activation by human cardiac fibroblast contraction. Cardiovasc Res 2014; 102:407–417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Kong P, Shinde AV, Su Y, Russo I, Chen B, Saxena A, Conway SJ, Graff JM, Frangogiannis NG. Opposing Actions of Fibroblast and Cardiomyocyte Smad3 Signaling in the Infarcted Myocardium. Circulation 2018; 137:707–724. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Dobaczewski M, Bujak M, Li N, Gonzalez-Quesada C, Mendoza LH, Wang XF, Frangogiannis NG. Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction. Circ Res 2010; 107:418–428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008; 456:980–984. [DOI] [PubMed] [Google Scholar]
- 63.Wang JW, Fontes MSC, Wang X, Chong SY, Kessler EL, Zhang YN, de Haan JJ, Arslan F, de Jager SCA, Timmers L, van Veen TAB, Lam CSP, Kleijn DPV. Leukocytic Toll-Like Receptor 2 Deficiency Preserves Cardiac Function And Reduces Fibrosis In Sustained Pressure Overload. Sci Rep 2017; 7:9193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Kain D, Amit U, Yagil C, Landa N, Naftali-Shani N, Molotski N, Aviv V, Feinberg MS, Goitein O, Kushnir T, Konen E, Epstein FH, Yagil Y, Leor J. Macrophages dictate the progression and manifestation of hypertensive heart disease. Int J Cardiol 2016; 203:381–395. [DOI] [PubMed] [Google Scholar]
- 65.Usher MG, Duan SZ, Ivaschenko CY, Frieler RA, Berger S, Schutz G, Lumeng CN, Mortensen RM. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J Clin Invest 2010; 120:3350–3364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Laroumanie F, Douin-Echinard V, Pozzo J, Lairez O, Tortosa F, Vinel C, Delage C, Calise D, Dutaur M, Parini A, Pizzinat N. CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload. Circulation 2014; 129:2111–2124. [DOI] [PubMed] [Google Scholar]
- 67.Nevers T, Salvador AM, Grodecki-Pena A, Knapp A, Velazquez F, Aronovitz M, Kapur NK, Karas RH, Blanton RM, Alcaide P. Left Ventricular T-Cell Recruitment Contributes to the Pathogenesis of Heart Failure. Circ Heart Fail 2015; 8:776–787. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Nevers T, Salvador AM, Velazquez F, Ngwenyama N, Carrillo-Salinas FJ, Aronovitz M, Blanton RM, Alcaide P. Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure. J Exp Med 2017; 214:3311–3329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Hara M, Ono K, Hwang MW, Iwasaki A, Okada M, Nakatani K, Sasayama S, Matsumori A. Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med 2002; 195:375–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Liao CH, Akazawa H, Tamagawa M, Ito K, Yasuda N, Kudo Y, Yamamoto R, Ozasa Y, Fujimoto M, Wang P, Nakauchi H, Nakaya H, Komuro I. Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts. J Clin Invest 2010; 120:242–253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.McDonald LT, Zile MR, Zhang Y, Van Laer AO, Baicu CF, Stroud RE, Jones JA, LaRue AC, Bradshaw AD. Increased macrophage-derived SPARC precedes collagen deposition in myocardial fibrosis. Am J Physiol Heart Circ Physiol 2018; 315:H92–H100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Levick SP, Melendez GC, Plante E, McLarty JL, Brower GL, Janicki JS. Cardiac mast cells: the centrepiece in adverse myocardial remodelling. Cardiovasc Res 2012; 89:12–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Wong VW, Paterno J, Sorkin M, Glotzbach JP, Levi K, Januszyk M, Rustad KC, Longaker MT, Gurtner GC. Mechanical force prolongs acute inflammation via T-cell-dependent pathways during scar formation. FASEB J 2011; 25:4498–4510. [DOI] [PubMed] [Google Scholar]
- 74.McWhorter FY, Davis CT, Liu WF. Physical and mechanical regulation of macrophage phenotype and function. Cell Mol Life Sci 2015; 72:1303–1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Scheraga RG, Abraham S, Niese KA, Southern BD, Grove LM, Hite RD, McDonald C, Hamilton TA, Olman MA. TRPV4 Mechanosensitive Ion Channel Regulates Lipopolysaccharide-Stimulated Macrophage Phagocytosis. J Immunol 2016; 196:428–436. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Shen JZ, Morgan J, Tesch GH, Rickard AJ, Chrissobolis S, Drummond GR, Fuller PJ, Young MJ. Cardiac Tissue Injury and Remodeling Is Dependent Upon MR Regulation of Activation Pathways in Cardiac Tissue Macrophages. Endocrinology 2016; 157:3213–3223. [DOI] [PubMed] [Google Scholar]
- 77.Rickard AJ, Morgan J, Tesch G, Funder JW, Fuller PJ, Young MJ. Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure. Hypertension 2009; 54:537–543. [DOI] [PubMed] [Google Scholar]
- 78.Li C, Sun XN, Zeng MR, Zheng XJ, Zhang YY, Wan Q, Zhang WC, Shi C, Du LJ, Ai TJ, Liu Y, Liu Y, Du LL, Yi Y, Yu Y, Duan SZ. Mineralocorticoid Receptor Deficiency in T Cells Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction Through Modulating T-Cell Activation. Hypertension 2017; 70:137–147. [DOI] [PubMed] [Google Scholar]
- 79.Salvador AM, Nevers T, Velazquez F, Aronovitz M, Wang B, Abadia Molina A, Jaffe IZ, Karas RH, Blanton RM, Alcaide P. Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Infiltration, Cardiac Remodeling, and Function in Pressure Overload-Induced Heart Failure. J Am Heart Assoc 2016; 5:e003126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Kuwahara F, Kai H, Tokuda K, Niiyama H, Tahara N, Kusaba K, Takemiya K, Jalalidin A, Koga M, Nagata T, Shibata R, Imaizumi T. Roles of intercellular adhesion molecule-1 in hypertensive cardiac remodeling. Hypertension 2003; 41:819–823. [DOI] [PubMed] [Google Scholar]
- 81.Suetomi T, Willeford A, Brand CS, Cho Y, Ross RS, Miyamoto S, Brown JH. Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca(2+)/Calmodulin-Dependent Protein Kinase II delta Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling. Circulation 2018; 138:2530–2544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Patel B, Ismahil MA, Hamid T, Bansal SS, Prabhu SD. Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure. PLoS One 2017; 12:e0170781. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Xia Y, Lee K, Li N, Corbett D, Mendoza L, Frangogiannis NG. Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload. Histochem Cell Biol 2009; 131:471–481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Li Y, Lui KO, Zhou B. Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases. Nat Rev Cardiol 2018. [DOI] [PubMed]
- 85.Adiarto S, Heiden S, Vignon-Zellweger N, Nakayama K, Yagi K, Yanagisawa M, Emoto N. ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy. Life Sci 2012; 91:651–657. [DOI] [PubMed] [Google Scholar]
- 86.Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, Henderson JM, Ebert BL, Humphreys BD. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 2015; 16:51–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Willeford A, Suetomi T, Nickle A, Hoffman HM, Miyamoto S, Heller Brown J. CaMKIIdelta-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis. JCI Insight 2018; 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Rickard AJ, Morgan J, Bienvenu LA, Fletcher EK, Cranston GA, Shen JZ, Reichelt ME, Delbridge LM, Young MJ. Cardiomyocyte mineralocorticoid receptors are essential for deoxycorticosterone/salt-mediated inflammation and cardiac fibrosis. Hypertension 2012; 60:1443–1450. [DOI] [PubMed] [Google Scholar]
- 89.Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA. Pivotal role of cardiomyocyte TGF-beta signaling in the murine pathological response to sustained pressure overload. J Clin Invest 2011; 121:2301–2312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 90.Bella J, Hulmes DJ. Fibrillar Collagens. Subcell Biochem 2017; 82:457–490. [DOI] [PubMed] [Google Scholar]
- 91.Khalil H, Kanisicak O, Prasad V, Correll RN, Fu X, Schips T, Vagnozzi RJ, Liu R, Huynh T, Lee SJ, Karch J, Molkentin JD. Fibroblast-specific TGF-beta-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest 2017; 127:3770–3783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Yonezawa T, Umemoto S, Fujii A, Katayama K, Matsuzaki M. Comparative effects of type 1 angiotensin II-receptor blockade with angiotensin-converting-enzyme inhibitor on left ventricular distensibility and collagen metabolism in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1996; 27:119–124. [DOI] [PubMed] [Google Scholar]
- 93.Baba HA, Iwai T, Bauer M, Irlbeck M, Schmid KW, Zimmer HG. Differential effects of angiotensin II receptor blockade on pressure-induced left ventricular hypertrophy and fibrosis in rats. J Mol Cell Cardiol 1999; 31:445–455. [DOI] [PubMed] [Google Scholar]
- 94.Brown L, Duce B, Miric G, Sernia C. Reversal of cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats by inhibition of the renin-angiotensin system. J Am Soc Nephrol 1999; 10 Suppl 11:S143–148. [PubMed] [Google Scholar]
- 95.Weinberg EO, Schoen FJ, George D, Kagaya Y, Douglas PS, Litwin SE, Schunkert H, Benedict CR, Lorell BH. Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis. Circulation 1994; 90:1410–1422. [DOI] [PubMed] [Google Scholar]
- 96.Tsutsumi Y, Matsubara H, Ohkubo N, Mori Y, Nozawa Y, Murasawa S, Kijima K, Maruyama K, Masaki H, Moriguchi Y, Shibasaki Y, Kamihata H, Inada M, Iwasaka T. Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression. Circ Res 1998; 83:1035–1046. [DOI] [PubMed] [Google Scholar]
- 97.Akishita M, Iwai M, Wu L, Zhang L, Ouchi Y, Dzau VJ, Horiuchi M. Inhibitory effect of angiotensin II type 2 receptor on coronary arterial remodeling after aortic banding in mice. Circulation 2000; 102:1684–1689. [DOI] [PubMed] [Google Scholar]
- 98.Mukherjee D, Sen S. Alteration of cardiac collagen phenotypes in hypertensive hypertrophy: role of blood pressure. J Mol Cell Cardiol 1993; 25:185–196. [DOI] [PubMed] [Google Scholar]
- 99.Echegaray K, Andreu I, Lazkano A, Villanueva I, Saenz A, Elizalde MR, Echeverria T, Lopez B, Garro A, Gonzalez A, Zubillaga E, Solla I, Sanz I, Gonzalez J, Elosegui-Artola A, Roca-Cusachs P, Diez J, Ravassa S, Querejeta R. Role of Myocardial Collagen in Severe Aortic Stenosis With Preserved Ejection Fraction and Symptoms of Heart Failure. Rev Esp Cardiol (Engl Ed) 2017; 70:832–840. [DOI] [PubMed] [Google Scholar]
- 100.Yamamoto K, Masuyama T, Sakata Y, Nishikawa N, Mano T, Yoshida J, Miwa T, Sugawara M, Yamaguchi Y, Ookawara T, Suzuki K, Hori M. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc Res 2002; 55:76–82. [DOI] [PubMed] [Google Scholar]
- 101.Norton GR, Tsotetsi J, Trifunovic B, Hartford C, Candy GP, Woodiwiss AJ. Myocardial stiffness is attributed to alterations in cross-linked collagen rather than total collagen or phenotypes in spontaneously hypertensive rats. Circulation 1997; 96:1991–1998. [DOI] [PubMed] [Google Scholar]
- 102.Fielitz J, Hein S, Mitrovic V, Pregla R, Zurbrugg HR, Warnecke C, Schaper J, Fleck E, Regitz-Zagrosek V. Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. J Am Coll Cardiol 2001; 37:1443–1449. [DOI] [PubMed] [Google Scholar]
- 103.Baicu CF, Zhang Y, Van Laer AO, Renaud L, Zile MR, Bradshaw AD. Effects of the absence of procollagen C-endopeptidase enhancer-2 on myocardial collagen accumulation in chronic pressure overload. Am J Physiol Heart Circ Physiol 2012; 303:H234–240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104.Bradshaw AD, Baicu CF, Rentz TJ, Van Laer AO, Boggs J, Lacy JM, Zile MR. Pressure overload-induced alterations in fibrillar collagen content and myocardial diastolic function: role of secreted protein acidic and rich in cysteine (SPARC) in post-synthetic procollagen processing. Circulation 2009; 119:269–280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105.Lopez B, Gonzalez A, Hermida N, Valencia F, de Teresa E, Diez J. Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects. Am J Physiol Heart Circ Physiol 2010; 299:H1–9. [DOI] [PubMed] [Google Scholar]
- 106.Yang J, Savvatis K, Kang JS, Fan P, Zhong H, Schwartz K, Barry V, Mikels-Vigdal A, Karpinski S, Kornyeyev D, Adamkewicz J, Feng X, Zhou Q, Shang C, Kumar P, Phan D, Kasner M, Lopez B, Diez J, Wright KC, Kovacs RL, Chen PS, Quertermous T, Smith V, Yao L, Tschope C, Chang CP. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nature communications 2016; 7:13710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Shinde AV, Dobaczewski M, de Haan JJ, Saxena A, Lee KK, Xia Y, Chen W, Su Y, Hanif W, Kaur Madahar I, Paulino VM, Melino G, Frangogiannis NG. Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling. Cardiovasc Res 2017; 113:892–905. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Shinde AV, Frangogiannis NG. Tissue transglutaminase in the pathogenesis of heart failure. Cell Death Differ 2018; 25:453–456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Shinde AV, Su Y, Palanski BA, Fujikura K, Garcia MJ, Frangogiannis NG. Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload. J Mol Cell Cardiol 2018; 117:36–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Lopez B, Querejeta R, Gonzalez A, Larman M, Diez J. Collagen cross-linking but not collagen amount associates with elevated filling pressures in hypertensive patients with stage C heart failure: potential role of lysyl oxidase. Hypertension 2012; 60:677–683. [DOI] [PubMed] [Google Scholar]
- 111.Lopez B, Ravassa S, Gonzalez A, Zubillaga E, Bonavila C, Berges M, Echegaray K, Beaumont J, Moreno MU, San Jose G, Larman M, Querejeta R, Diez J. Myocardial Collagen Cross-Linking Is Associated With Heart Failure Hospitalization in Patients With Hypertensive Heart Failure. J Am Coll Cardiol 2016; 67:251–260. [DOI] [PubMed] [Google Scholar]
- 112.Woodiwiss AJ, Tsotetsi OJ, Sprott S, Lancaster EJ, Mela T, Chung ES, Meyer TE, Norton GR. Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction. Circulation 2001; 103:155–160. [DOI] [PubMed] [Google Scholar]
- 113.Shamhart PE, Meszaros JG. Non-fibrillar collagens: key mediators of post-infarction cardiac remodeling? J Mol Cell Cardiol 2010; 48:530–537. [DOI] [PubMed] [Google Scholar]
- 114.Sabatelli P, Gualandi F, Gara SK, Grumati P, Zamparelli A, Martoni E, Pellegrini C, Merlini L, Ferlini A, Bonaldo P, Maraldi NM, Paulsson M, Squarzoni S, Wagener R. Expression of collagen VI alpha5 and alpha6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis. Matrix Biol 2012; 31:187–196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.Sanchez-Lopez E, Rodriguez-Vita J, Cartier C, Ruperez M, Esteban V, Carvajal G, Rodrigues-Diez R, Plaza JJ, Egido J, Ruiz-Ortega M. Inhibitory effect of interleukin-1beta on angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells. Am J Physiol Renal Physiol 2008; 294:F149–160. [DOI] [PubMed] [Google Scholar]
- 116.Gil-Cayuela C, Rosello LE, Ortega A, Tarazon E, Trivino JC, Martinez-Dolz L, Gonzalez-Juanatey JR, Lago F, Portoles M, Rivera M. New Altered Non-Fibrillar Collagens in Human Dilated Cardiomyopathy: Role in the Remodeling Process. PLoS One 2016; 11:e0168130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Chapman D, Weber KT, Eghbali M. Regulation of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in pressure overloaded rat myocardium. Circ Res 1990; 67:787–794. [DOI] [PubMed] [Google Scholar]
- 118.Naugle JE, Olson ER, Zhang X, Mase SE, Pilati CF, Maron MB, Folkesson HG, Horne WI, Doane KJ, Meszaros JG. Type VI collagen induces cardiac myofibroblast differentiation: implications for postinfarction remodeling. Am J Physiol Heart Circ Physiol 2006; 290:H323–330. [DOI] [PubMed] [Google Scholar]
- 119.Skrbic B, Engebretsen KV, Strand ME, Lunde IG, Herum KM, Marstein HS, Sjaastad I, Lunde PK, Carlson CR, Christensen G, Bjornstad JL, Tonnessen T. Lack of collagen VIII reduces fibrosis and promotes early mortality and cardiac dilatation in pressure overload in mice. Cardiovasc Res 2015; 106:32–42. [DOI] [PubMed] [Google Scholar]
- 120.Luther DJ, Thodeti CK, Shamhart PE, Adapala RK, Hodnichak C, Weihrauch D, Bonaldo P, Chilian WM, Meszaros JG. Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction. Circ Res 2012; 110:851–856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88:277–285. [DOI] [PubMed] [Google Scholar]
- 122.Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev 2012; 92:635–688. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Christensen G, Herum KM, Lunde IG. Sweet, yet underappreciated: Proteoglycans and extracellular matrix remodeling in heart disease. Matrix Biol 2018. [DOI] [PubMed]
- 124.Valiente-Alandi I, Schafer AE, Blaxall BC. Extracellular matrix-mediated cellular communication in the heart. J Mol Cell Cardiol 2016; 91:228–237. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 125.Samuel JL, Barrieux A, Dufour S, Dubus I, Contard F, Koteliansky V, Farhadian F, Marotte F, Thiery JP, Rappaport L. Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload. J Clin Invest 1991; 88:1737–1746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Arslan F, Smeets MB, Riem Vis PW, Karper JC, Quax PH, Bongartz LG, Peters JH, Hoefer IE, Doevendans PA, Pasterkamp G, de Kleijn DP. Lack of fibronectin-EDA promotes survival and prevents adverse remodeling and heart function deterioration after myocardial infarction. Circ Res 2011; 108:582–592. [DOI] [PubMed] [Google Scholar]
- 127.Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol 1998; 142:873–881. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 128.Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol 2007; 170:1807–1816. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Klingberg F, Chau G, Walraven M, Boo S, Koehler A, Chow ML, Olsen AL, Im M, Lodyga M, Wells RG, White ES, Hinz B. The fibronectin ED-A domain enhances recruitment of latent TGF-beta-binding protein-1 to the fibroblast matrix. J Cell Sci 2018; 131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Fukuda T, Yoshida N, Kataoka Y, Manabe R, Mizuno-Horikawa Y, Sato M, Kuriyama K, Yasui N, Sekiguchi K. Mice lacking the EDB segment of fibronectin develop normally but exhibit reduced cell growth and fibronectin matrix assembly in vitro. Cancer Res 2002; 62:5603–5610. [PubMed] [Google Scholar]
- 131.Valiente-Alandi I, Potter SJ, Salvador AM, Schafer AE, Schips T, Carrillo-Salinas F, Gibson AM, Nieman ML, Perkins C, Sargent MA, Huo J, Lorenz JN, DeFalco T, Molkentin JD, Alcaide P, Blaxall BC. Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure. Circulation 2018. [DOI] [PMC free article] [PubMed]
- 132.Sottile J, Hocking DC. Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell-matrix adhesions. Mol Biol Cell 2002; 13:3546–3559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Frangogiannis NG. The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Invest 2017; 127:1600–1612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 134.Bornstein P Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J Cell Biol 1995; 130:503–506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135.Bornstein P Matricellular proteins: an overview. J Cell Commun Signal 2009; 3:163–165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 136.Xia Y, Dobaczewski M, Gonzalez-Quesada C, Chen W, Biernacka A, Li N, Lee DW, Frangogiannis NG. Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism. Hypertension 2011; 58:902–911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137.Zohar R, Zhu B, Liu P, Sodek J, McCulloch CA. Increased cell death in osteopontin-deficient cardiac fibroblasts occurs by a caspase-3-independent pathway. Am J Physiol Heart Circ Physiol 2004; 287:H1730–1739. [DOI] [PubMed] [Google Scholar]
- 138.Shimazaki M, Nakamura K, Kii I, Kashima T, Amizuka N, Li M, Saito M, Fukuda K, Nishiyama T, Kitajima S, Saga Y, Fukayama M, Sata M, Kudo A. Periostin is essential for cardiac healing after acute myocardial infarction. J Exp Med 2008; 205:295–303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 139.Lorenzen JM, Schauerte C, Hubner A, Kolling M, Martino F, Scherf K, Batkai S, Zimmer K, Foinquinos A, Kaucsar T, Fiedler J, Kumarswamy R, Bang C, Hartmann D, Gupta SK, Kielstein J, Jungmann A, Katus HA, Weidemann F, Muller OJ, Haller H, Thum T. Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis. Eur Heart J 2015; 36:2184–2196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 140.Frolova EG, Sopko N, Blech L, Popovic ZB, Li J, Vasanji A, Drumm C, Krukovets I, Jain MK, Penn MS, Plow EF, Stenina OI. Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload. Faseb J 2012; 26:2363–2373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141.Jeong D, Lee MA, Li Y, Yang DK, Kho C, Oh JG, Hong G, Lee A, Song MH, LaRocca TJ, Chen J, Liang L, Mitsuyama S, D’Escamard V, Kovacic JC, Kwak TH, Hajjar RJ, Park WJ. Matricellular Protein CCN5 Reverses Established Cardiac Fibrosis. J Am Coll Cardiol 2016; 67:1556–1568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142.Abbadi D, Laroumanie F, Bizou M, Pozzo J, Daviaud D, Delage C, Calise D, Gaits-Iacovoni F, Dutaur M, Tortosa F, Renaud-Gabardos E, Douin-Echinard V, Prats AC, Roncalli J, Parini A, Pizzinat N. Local production of tenascin-C acts as a trigger for monocyte/macrophage recruitment that provokes cardiac dysfunction. Cardiovasc Res 2018; 114:123–137. [DOI] [PubMed] [Google Scholar]
- 143.Shimojo N, Hashizume R, Kanayama K, Hara M, Suzuki Y, Nishioka T, Hiroe M, Yoshida T, Imanaka-Yoshida K. Tenascin-C May Accelerate Cardiac Fibrosis by Activating Macrophages via the Integrin alphaVbeta3/Nuclear Factor-kappaB/Interleukin-6 Axis. Hypertension 2015; 66:757–766. [DOI] [PubMed] [Google Scholar]
- 144.Song L, Wang L, Li F, Yukht A, Qin M, Ruther H, Yang M, Chaux A, Shah PK, Sharifi BG. Bone Marrow-Derived Tenascin-C Attenuates Cardiac Hypertrophy by Controlling Inflammation. J Am Coll Cardiol 2017; 70:1601–1615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Cingolani OH, Kirk JA, Seo K, Koitabashi N, Lee DI, Ramirez-Correa G, Bedja D, Barth AS, Moens AL, Kass DA. Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle. Circ Res 2011; 109:1410–1414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 146.Swinnen M, Vanhoutte D, Van Almen GC, Hamdani N, Schellings MW, D’Hooge J, Van der Velden J, Weaver MS, Sage EH, Bornstein P, Verheyen FK, VandenDriessche T, Chuah MK, Westermann D, Paulus WJ, Van de Werf F, Schroen B, Carmeliet P, Pinto YM, Heymans S. Absence of thrombospondin-2 causes age-related dilated cardiomyopathy. Circulation 2009; 120:1585–1597. [DOI] [PubMed] [Google Scholar]
- 147.Rosini S, Pugh N, Bonna AM, Hulmes DJS, Farndale RW, Adams JC. Thrombospondin-1 promotes matrix homeostasis by interacting with collagen and lysyl oxidase precursors and collagen cross-linking sites. Sci Signal 2018; 11. [DOI] [PubMed] [Google Scholar]
- 148.Calabro NE, Kristofik NJ, Kyriakides TR. Thrombospondin-2 and extracellular matrix assembly. Biochim Biophys Acta 2014; 1840:2396–2402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 149.Lynch JM, Maillet M, Vanhoutte D, Schloemer A, Sargent MA, Blair NS, Lynch KA, Okada T, Aronow BJ, Osinska H, Prywes R, Lorenz JN, Mori K, Lawler J, Robbins J, Molkentin JD. A thrombospondin-dependent pathway for a protective ER stress response. Cell 2012; 149:1257–1268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 150.Schips TG, Vanhoutte D, Vo A, Correll RN, Brody MJ, Khalil H, Karch J, Tjondrokoesoemo A, Sargent MA, Maillet M, Ross RS, Molkentin JD. Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability. Nature communications 2019; 10:76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.Iozzo RV, Schaefer L. Proteoglycan form and function: A comprehensive nomenclature of proteoglycans. Matrix Biol 2015; 42:11–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Zhao RR, Ackers-Johnson M, Stenzig J, Chen C, Ding T, Zhou Y, Wang P, Ng SL, Li PY, Teo G, Rudd PM, Fawcett JW, Foo RSY. Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling. Circulation 2018. [DOI] [PubMed]
- 153.Heimer R, Bashey RI, Kyle J, Jimenez SA. TGF-beta modulates the synthesis of proteoglycans by myocardial fibroblasts in culture. J Mol Cell Cardiol 1995; 27:2191–2198. [DOI] [PubMed] [Google Scholar]
- 154.Tiede K, Stoter K, Petrik C, Chen WB, Ungefroren H, Kruse ML, Stoll M, Unger T, Fischer JW. Angiotensin II AT(1)-receptor induces biglycan in neonatal cardiac fibroblasts via autocrine release of TGFbeta in vitro. Cardiovasc Res 2003; 60:538–546. [DOI] [PubMed] [Google Scholar]
- 155.Engebretsen KV, Lunde IG, Strand ME, Waehre A, Sjaastad I, Marstein HS, Skrbic B, Dahl CP, Askevold ET, Christensen G, Bjornstad JL, Tonnessen T. Lumican is increased in experimental and clinical heart failure, and its production by cardiac fibroblasts is induced by mechanical and proinflammatory stimuli. FEBS J 2013; 280:2382–2398. [DOI] [PubMed] [Google Scholar]
- 156.Beetz N, Rommel C, Schnick T, Neumann E, Lother A, Monroy-Ordonez EB, Zeeb M, Preissl S, Gilsbach R, Melchior-Becker A, Rylski B, Stoll M, Schaefer L, Beyersdorf F, Stiller B, Hein L. Ablation of biglycan attenuates cardiac hypertrophy and fibrosis after left ventricular pressure overload. J Mol Cell Cardiol 2016; 101:145–155. [DOI] [PubMed] [Google Scholar]
- 157.Yan W, Wang P, Zhao CX, Tang J, Xiao X, Wang DW. Decorin gene delivery inhibits cardiac fibrosis in spontaneously hypertensive rats by modulation of transforming growth factor-beta/Smad and p38 mitogen-activated protein kinase signaling pathways. Hum Gene Ther 2009; 20:1190–1200. [DOI] [PubMed] [Google Scholar]
- 158.Chen SW, Tung YC, Jung SM, Chu Y, Lin PJ, Kao WW, Chu PH. Lumican-null mice are susceptible to aging and isoproterenol-induced myocardial fibrosis. Biochem Biophys Res Commun 2017; 482:1304–1311. [DOI] [PubMed] [Google Scholar]
- 159.Deckx S, Heggermont W, Carai P, Rienks M, Dresselaers T, Himmelreich U, van Leeuwen R, Lommen W, van der Velden J, Gonzalez A, Diez J, Papageorgiou AP, Heymans S. Osteoglycin prevents the development of age-related diastolic dysfunction during pressure overload by reducing cardiac fibrosis and inflammation. Matrix Biol 2018; 66:110–124. [DOI] [PubMed] [Google Scholar]
- 160.Barallobre-Barreiro J, Gupta SK, Zoccarato A, Kitazume-Taneike R, Fava M, Yin X, Werner T, Hirt MN, Zampetaki A, Viviano A, Chong M, Bern M, Kourliouros A, Domenech N, Willeit P, Shah AM, Jahangiri M, Schaefer L, Fischer JW, Iozzo RV, Viner R, Thum T, Heineke J, Kichler A, Otsu K, Mayr M. Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation. Circulation 2016; 134:817–832. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 161.Borg KT, Burgess W, Terracio L, Borg TK. Expression of metalloproteases by cardiac myocytes and fibroblasts in vitro. Cardiovasc Pathol 1997; 6:261–269. [DOI] [PubMed] [Google Scholar]
- 162.DeLeon-Pennell KY, Meschiari CA, Jung M, Lindsey ML. Matrix Metalloproteinases in Myocardial Infarction and Heart Failure. Prog Mol Biol Transl Sci 2017; 147:75–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.Goldsmith EC, Bradshaw AD, Spinale FG. Cellular mechanisms of tissue fibrosis. 2. Contributory pathways leading to myocardial fibrosis: moving beyond collagen expression. Am J Physiol Cell Physiol 2013; 304:C393–402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 164.Takawale A, Zhang P, Azad A, Wang W, Wang X, Murray AG, Kassiri Z. Myocardial overexpression of TIMP3 after myocardial infarction exerts beneficial effects by promoting angiogenesis and suppressing early proteolysis. Am J Physiol Heart Circ Physiol 2017; 313:H224–H236. [DOI] [PubMed] [Google Scholar]
- 165.Takawale A, Zhang P, Patel VB, Wang X, Oudit G, Kassiri Z. Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63-Integrin beta1 Interaction. Hypertension 2017; 69:1092–1103. [DOI] [PubMed] [Google Scholar]
- 166.Spinale FG, Janicki JS, Zile MR. Membrane-associated matrix proteolysis and heart failure. Circ Res 2013; 112:195–208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 167.Bonnin CM, Sparrow MP, Taylor RR. Collagen synthesis and content in right ventricular hypertrophy in the dog. Am J Physiol 1981; 241:H708–713. [DOI] [PubMed] [Google Scholar]
- 168.Skosey JL, Zak R, Martin AF, Aschenbrenner V, Rabinowitz M. Biochemical correlates of cardiac hypertrophy. V. Labeling of collagen, myosin, and nuclear DNA during experimental myocardial hypertrophy in the rat. Circ Res 1972; 31:145–157. [DOI] [PubMed] [Google Scholar]
- 169.Lopez B, Gonzalez A, Querejeta R, Larman M, Diez J. Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol 2006; 48:89–96. [DOI] [PubMed] [Google Scholar]
- 170.Awad AE, Kandalam V, Chakrabarti S, Wang X, Penninger JM, Davidge ST, Oudit GY, Kassiri Z. Tumor necrosis factor induces matrix metalloproteinases in cardiomyocytes and cardiofibroblasts differentially via superoxide production in a PI3Kgamma-dependent manner. Am J Physiol Cell Physiol 2010; 298:C679–692. [DOI] [PubMed] [Google Scholar]
- 171.Szardien S, Nef HM, Troidl C, Willmer M, Voss S, Liebetrau C, Hoffmann J, Rolf A, Rixe J, Elsasser A, Hamm CW, Mollmann H. Bone marrow-derived cells contribute to cell turnover in aging murine hearts. Int J Mol Med 2012; 30:283–287. [DOI] [PubMed] [Google Scholar]
- 172.Saxena A, Chen W, Su Y, Rai V, Uche OU, Li N, Frangogiannis NG. IL-1 Induces Proinflammatory Leukocyte Infiltration and Regulates Fibroblast Phenotype in the Infarcted Myocardium. J Immunol 2013; 191:4838–4848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 173.McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 2002; 100:1160–1167. [PubMed] [Google Scholar]
- 174.McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I, Overall CM. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 2001; 276:43503–43508. [DOI] [PubMed] [Google Scholar]
- 175.Lee EJ, Han JE, Woo MS, Shin JA, Park EM, Kang JL, Moon PG, Baek MC, Son WS, Ko YT, Choi JW, Kim HS. Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-alpha activation. J Immunol 2014; 193:2384–2393. [DOI] [PubMed] [Google Scholar]
- 176.D’Angelo M, Billings PC, Pacifici M, Leboy PS, Kirsch T. Authentic matrix vesicles contain active metalloproteases (MMP). a role for matrix vesicle-associated MMP-13 in activation of transforming growth factor-beta. J Biol Chem 2001; 276:11347–11353. [DOI] [PubMed] [Google Scholar]
- 177.Deryugina EI, Ratnikov BI, Postnova TI, Rozanov DV, Strongin AY. Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J Biol Chem 2002; 277:9749–9756. [DOI] [PubMed] [Google Scholar]
- 178.Endo K, Takino T, Miyamori H, Kinsen H, Yoshizaki T, Furukawa M, Sato H. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J Biol Chem 2003; 278:40764–40770. [DOI] [PubMed] [Google Scholar]
- 179.Jobin PG, Butler GS, Overall CM. New intracellular activities of matrix metalloproteinases shine in the moonlight. Biochim Biophys Acta 2017; 1864:2043–2055. [DOI] [PubMed] [Google Scholar]
- 180.Sawicki G, Leon H, Sawicka J, Sariahmetoglu M, Schulze CJ, Scott PG, Szczesna-Cordary D, Schulz R. Degradation of myosin light chain in isolated rat hearts subjected to ischemia-reperfusion injury: a new intracellular target for matrix metalloproteinase-2. Circulation 2005; 112:544–552. [DOI] [PubMed] [Google Scholar]
- 181.de Castro Bras LE, Cates CA, DeLeon-Pennell KY, Ma Y, Iyer RP, Halade GV, Yabluchanskiy A, Fields GB, Weintraub ST, Lindsey ML. Citrate synthase is a novel in vivo matrix metalloproteinase-9 substrate that regulates mitochondrial function in the postmyocardial infarction left ventricle. Antioxid Redox Signal 2014; 21:1974–1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 182.Gonzalez A, Lopez B, Querejeta R, Zubillaga E, Echeverria T, Diez J. Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction. Hypertension 2010; 55:1418–1424. [DOI] [PubMed] [Google Scholar]
- 183.Mead TJ, Apte SS. ADAMTS proteins in human disorders. Matrix Biol 2018; 71–72:225–239. [DOI] [PMC free article] [PubMed]
- 184.Zhong S, Khalil RA. A Disintegrin and Metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS) family in vascular biology and disease. Biochem Pharmacol 2019; 164:188–204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 185.Fan D, Takawale A, Shen M, Samokhvalov V, Basu R, Patel V, Wang X, Fernandez-Patron C, Seubert JM, Oudit GY, Kassiri Z. A Disintegrin and Metalloprotease-17 Regulates Pressure Overload-Induced Myocardial Hypertrophy and Dysfunction Through Proteolytic Processing of Integrin beta1. Hypertension 2016; 68:937–948. [DOI] [PubMed] [Google Scholar]
- 186.Wang X, Chen W, Zhang J, Khan A, Li L, Huang F, Qiu Z, Wang L, Chen X. Critical Role of ADAMTS2 (A Disintegrin and Metalloproteinase With Thrombospondin Motifs 2) in Cardiac Hypertrophy Induced by Pressure Overload. Hypertension 2017; 69:1060–1069. [DOI] [PubMed] [Google Scholar]
- 187.Zheng J, Chen Y, Pat B, Dell’italia LA, Tillson M, Dillon AR, Powell PC, Shi K, Shah N, Denney T, Husain A, Dell’Italia LJ. Microarray identifies extensive downregulation of noncollagen extracellular matrix and profibrotic growth factor genes in chronic isolated mitral regurgitation in the dog. Circulation 2009; 119:2086–2095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 188.Nagatomo Y, Carabello BA, Coker ML, McDermott PJ, Nemoto S, Hamawaki M, Spinale FG. Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control. Am J Physiol Heart Circ Physiol 2000; 278:H151–161. [DOI] [PubMed] [Google Scholar]
- 189.Corporan D, Onohara D, Hernandez-Merlo R, Sielicka A, Padala M. Temporal Changes in Myocardial Collagen, Matrix Metalloproteinases and their Inhibitors in Experimental Chronic Mitral Regurgitation in Rodents. Am J Physiol Heart Circ Physiol 2018. [DOI] [PMC free article] [PubMed]
- 190.Childers RC, Sunyecz I, West TA, Cismowski MJ, Lucchesi PA, Gooch KJ. Role of the Cytoskeleton in the Development of a Hypofibrotic Cardiac Fibroblast Phenotype in Volume Overload Heart Failure. Am J Physiol Heart Circ Physiol 2018; 2018. December 21. doi: 10.1152/ajpheart.00095.2018. [DOI] [PubMed] [Google Scholar]
- 191.Fu L, Wei CC, Powell PC, Bradley WE, Collawn JF, Dell’Italia LJ. Volume overload induces autophagic degradation of procollagen in cardiac fibroblasts. J Mol Cell Cardiol 2015; 89:241–250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 192.Janicki JS, Brower GL, Gardner JD, Forman MF, Stewart JA Jr., Murray DB, Chancey AL. Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload. Cardiovasc Res 2006; 69:657–665. [DOI] [PubMed] [Google Scholar]
- 193.Cheng WP, Wang BW, Lo HM, Shyu KG. Mechanical Stretch Induces Apoptosis Regulator TRB3 in Cultured Cardiomyocytes and Volume-Overloaded Heart. PLoS One 2015; 10:e0123235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 194.Pfeiffer ER, Wright AT, Edwards AG, Stowe JC, McNall K, Tan J, Niesman I, Patel HH, Roth DM, Omens JH, McCulloch AD. Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing. J Mol Cell Cardiol 2014; 76:265–274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 195.Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 2010; 48:504–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 196.Dobaczewski M, Bujak M, Zymek P, Ren G, Entman ML, Frangogiannis NG. Extracellular matrix remodeling in canine and mouse myocardial infarcts. Cell Tissue Res 2006; 324:475–488. [DOI] [PubMed] [Google Scholar]
- 197.Cleutjens JP, Verluyten MJ, Smiths JF, Daemen MJ. Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol 1995; 147:325–338. [PMC free article] [PubMed] [Google Scholar]
- 198.Fu X, Khalil H, Kanisicak O, Boyer JG, Vagnozzi RJ, Maliken BD, Sargent MA, Prasad V, Valiente-Alandi I, Blaxall BC, Molkentin JD. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J Clin Invest 2018; 128:2127–2143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 199.Frangogiannis NG, Ren G, Dewald O, Zymek P, Haudek S, Koerting A, Winkelmann K, Michael LH, Lawler J, Entman ML. The critical role of endogenous Thrombospondin (TSP)-1 in preventing expansion of healing myocardial infarcts. Circulation 2005; 111:2935–2942. [DOI] [PubMed] [Google Scholar]
- 200.Schellings MW, Vanhoutte D, Swinnen M, Cleutjens JP, Debets J, van Leeuwen RE, d’Hooge J, Van de Werf F, Carmeliet P, Pinto YM, Sage EH, Heymans S. Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction. J Exp Med 2009; 206:113–123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 201.Van Aelst LN, Voss S, Carai P, Van Leeuwen R, Vanhoutte D, Sanders-van Wijk S, Eurlings L, Swinnen M, Verheyen FK, Verbeken E, Nef H, Troidl C, Cook SA, Brunner-La Rocca HP, Mollmann H, Papageorgiou AP, Heymans S. Osteoglycin prevents cardiac dilatation and dysfunction after myocardial infarction through infarct collagen strengthening. Circ Res 2015; 116:425–436. [DOI] [PubMed] [Google Scholar]
- 202.Sager HB, Hulsmans M, Lavine KJ, Beltrami Moreira MB, Heidt T, Courties G, Sun Y, Iwamoto Y, Tricot B, Khan OF, Dahlman JE, Borodovsky A, Fitzgerald K, Anderson DG, Weissleder R, Libby P, Swirski FK, Nahrendorf M. Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure. Circ Res 2016. [DOI] [PMC free article] [PubMed]
- 203.Chen B, Frangogiannis NG. Macrophages in the Remodeling Failing Heart. Circ Res 2016; 119:776–778. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 204.Soejima H, Ogawa H, Sakamoto T, Miyamoto S, Kajiwara I, Kojima S, Hokamaki J, Sugiyama S, Yoshimura M, Suefuji H, Miyao Y, Fujimoto K, Miyagi H, Kishikawa H. Increased serum matrix metalloproteinase-1 concentration predicts advanced left ventricular remodeling in patients with acute myocardial infarction. Circ J 2003; 67:301–304. [DOI] [PubMed] [Google Scholar]
- 205.Wagner DR, Delagardelle C, Ernens I, Rouy D, Vaillant M, Beissel J. Matrix metalloproteinase-9 is a marker of heart failure after acute myocardial infarction. J Card Fail 2006; 12:66–72. [DOI] [PubMed] [Google Scholar]
- 206.Lu L, Gunja-Smith Z, Woessner JF, Ursell PC, Nissen T, Galardy RE, Xu Y, Zhu P, Schwartz GG. Matrix metalloproteinases and collagen ultrastructure in moderate myocardial ischemia and reperfusion in vivo. Am J Physiol Heart Circ Physiol 2000; 279:H601–609. [DOI] [PubMed] [Google Scholar]
- 207.Dewald O, Frangogiannis NG, Zoerlein M, Duerr GD, Klemm C, Knuefermann P, Taffet G, Michael LH, Crapo JD, Welz A, Entman ML. Development of murine ischemic cardiomyopathy is associated with a transient inflammatory reaction and depends on reactive oxygen species. Proc Natl Acad Sci U S A 2003; 100:2700–2705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 208.Lalu MM, Pasini E, Schulze CJ, Ferrari-Vivaldi M, Ferrari-Vivaldi G, Bachetti T, Schulz R. Ischaemia-reperfusion injury activates matrix metalloproteinases in the human heart. Eur Heart J 2005; 26:27–35. [DOI] [PubMed] [Google Scholar]
- 209.Spinale FG, Coker ML, Heung LJ, Bond BR, Gunasinghe HR, Etoh T, Goldberg AT, Zellner JL, Crumbley AJ. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 2000; 102:1944–1949. [DOI] [PubMed] [Google Scholar]
- 210.Reinhardt D, Sigusch HH, Hensse J, Tyagi SC, Korfer R, Figulla HR. Cardiac remodelling in end stage heart failure: upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP. Heart 2002; 88:525–530. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 211.Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, Rosenblum W, Kormos RL, Feldman AM. Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 2001; 104:1147–1152. [DOI] [PubMed] [Google Scholar]
- 212.Frangogiannis NG, Shimoni S, Chang SM, Ren G, Dewald O, Gersch C, Shan K, Aggeli C, Reardon M, Letsou GV, Espada R, Ramchandani M, Entman ML, Zoghbi WA. Active interstitial remodeling: an important process in the hibernating human myocardium. J Am Coll Cardiol 2002; 39:1468–1474. [DOI] [PubMed] [Google Scholar]
- 213.Frangogiannis NG, Shimoni S, Chang SM, Ren G, Shan K, Aggeli C, Reardon MJ, Letsou GV, Espada R, Ramchandani M, Entman ML, Zoghbi WA. Evidence for an active inflammatory process in the hibernating human myocardium. Am J Pathol 2002; 160:1425–1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 214.Alex L, Russo I, Holoborodko V, Frangogiannis NG. Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction. Am J Physiol Heart Circ Physiol 2018; 315:H934–H949. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 215.Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, Haider B. Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest 1977; 60:884–899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 216.Russo I, Frangogiannis NG. Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol 2016; 90:84–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 217.Gonzalez-Quesada C, Cavalera M, Biernacka A, Kong P, Lee DW, Saxena A, Frunza O, Dobaczewski M, Shinde A, Frangogiannis NG. Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation. Circ Res 2013; 113:1331–1344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 218.Kong P, Gonzalez-Quesada C, Li N, Cavalera M, Lee DW, Frangogiannis NG. Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation. Am J Physiol Endocrinol Metab 2013; 305:E439–450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 219.Biernacka A, Cavalera M, Wang J, Russo I, Shinde A, Kong P, Gonzalez-Quesada C, Rai V, Dobaczewski M, Lee DW, Wang XF, Frangogiannis NG. Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice. Circ Heart Fail 2015; 8:788–798. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 220.Wolffenbuttel BH, Boulanger CM, Crijns FR, Huijberts MS, Poitevin P, Swennen GN, Vasan S, Egan JJ, Ulrich P, Cerami A, Levy BI. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci U S A 1998; 95:4630–4634. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 221.Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med 2002; 347:305–313. [DOI] [PubMed] [Google Scholar]
- 222.Packer M, Kitzman DW. Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2. JACC Heart Fail 2018. [DOI] [PubMed]
- 223.Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction. Circulation 2017; 136:6–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 224.Buckley LF, Canada JM, Del Buono MG, Carbone S, Trankle CR, Billingsley H, Kadariya D, Arena R, Van Tassell BW, Abbate A. Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction. ESC Heart Fail 2018; 5:372–378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 225.Packer M Derangements in adrenergic-adipokine signalling establish a neurohormonal basis for obesity-related heart failure with a preserved ejection fraction. Eur J Heart Fail 2018; 20:873–878. [DOI] [PubMed] [Google Scholar]
- 226.Kenny HC, Abel ED. Heart Failure in Type 2 Diabetes Mellitus. Circ Res 2019; 124:121–141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 227.Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res 2018; 122:624–638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 228.Eghbali M, Eghbali M, Robinson TF, Seifter S, Blumenfeld OO. Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc Res 1989; 23:723–729. [DOI] [PubMed] [Google Scholar]
- 229.Gazoti Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R. Age related changes of the collagen network of the human heart. Mech Ageing Dev 2001; 122:1049–1058. [DOI] [PubMed] [Google Scholar]
- 230.de Souza RR. Aging of myocardial collagen. Biogerontology 2002; 3:325–335. [DOI] [PubMed] [Google Scholar]
- 231.Mays PK, McAnulty RJ, Campa JS, Laurent GJ. Age-related changes in collagen synthesis and degradation in rat tissues. Importance of degradation of newly synthesized collagen in regulating collagen production. Biochem J 1991; 276 ( Pt 2):307–313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 232.Besse S, Robert V, Assayag P, Delcayre C, Swynghedauw B. Nonsynchronous changes in myocardial collagen mRNA and protein during aging: effect of DOCA-salt hypertension. Am J Physiol 1994; 267:H2237–2244. [DOI] [PubMed] [Google Scholar]
- 233.Annoni G, Luvara G, Arosio B, Gagliano N, Fiordaliso F, Santambrogio D, Jeremic G, Mircoli L, Latini R, Vergani C, Masson S. Age-dependent expression of fibrosis-related genes and collagen deposition in the rat myocardium. Mech Ageing Dev 1998; 101:57–72. [DOI] [PubMed] [Google Scholar]
- 234.Robert V, Besse S, Sabri A, Silvestre JS, Assayag P, Nguyen VT, Swynghedauw B, Delcayre C. Differential regulation of matrix metalloproteinases associated with aging and hypertension in the rat heart. Lab Invest 1997; 76:729–738. [PubMed] [Google Scholar]
- 235.Thomas DP, Cotter TA, Li X, McCormick RJ, Gosselin LE. Exercise training attenuates aging-associated increases in collagen and collagen crosslinking of the left but not the right ventricle in the rat. Eur J Appl Physiol 2001; 85:164–169. [DOI] [PubMed] [Google Scholar]
- 236.Biernacka A, Frangogiannis NG. Aging and Cardiac Fibrosis. Aging Dis 2011; 2:158–173. [PMC free article] [PubMed] [Google Scholar]
- 237.Cahill TJ, Ashrafian H, Watkins H. Genetic cardiomyopathies causing heart failure. Circ Res 2013; 113:660–675. [DOI] [PubMed] [Google Scholar]
- 238.Hookana E, Junttila MJ, Puurunen VP, Tikkanen JT, Kaikkonen KS, Kortelainen ML, Myerburg RJ, Huikuri HV. Causes of nonischemic sudden cardiac death in the current era. Heart Rhythm 2011; 8:1570–1575. [DOI] [PubMed] [Google Scholar]
- 239.Junttila MJ, Holmstrom L, Pylkas K, Mantere T, Kaikkonen K, Porvari K, Kortelainen ML, Pakanen L, Kerkela R, Myerburg RJ, Huikuri HV. Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders. Circulation 2018; 137:2716–2726. [DOI] [PubMed] [Google Scholar]
- 240.Flevaris P, Khan SS, Eren M, Schuldt AJT, Shah SJ, Lee DC, Gupta S, Shapiro AD, Burridge PW, Ghosh AK, Vaughan DE. Plasminogen Activator Inhibitor Type I Controls Cardiomyocyte Transforming Growth Factor-beta and Cardiac Fibrosis. Circulation 2017; 136:664–679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 241.Ortiz-Genga MF, Cuenca S, Dal Ferro M, Zorio E, Salgado-Aranda R, Climent V, Padron-Barthe L, Duro-Aguado I, Jimenez-Jaimez J, Hidalgo-Olivares VM, Garcia-Campo E, Lanzillo C, Suarez-Mier MP, Yonath H, Marcos-Alonso S, Ochoa JP, Santome JL, Garcia-Giustiniani D, Rodriguez-Garrido JL, Dominguez F, Merlo M, Palomino J, Pena ML, Trujillo JP, Martin-Vila A, Stolfo D, Molina P, Lara-Pezzi E, Calvo-Iglesias FE, Nof E, Calo L, Barriales-Villa R, Gimeno-Blanes JR, Arad M, Garcia-Pavia P, Monserrat L. Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies. J Am Coll Cardiol 2016; 68:2440–2451. [DOI] [PubMed] [Google Scholar]
- 242.Factor SM, Butany J, Sole MJ, Wigle ED, Williams WC, Rojkind M. Pathologic fibrosis and matrix connective tissue in the subaortic myocardium of patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1991; 17:1343–1351. [DOI] [PubMed] [Google Scholar]
- 243.O’Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage R, Webb J, Kulkarni M, Dawson D, Sulaibeekh L, Chandrasekaran B, Bucciarelli-Ducci C, Pasquale F, Cowie MR, McKenna WJ, Sheppard MN, Elliott PM, Pennell DJ, Prasad SK. Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Cardiol 2010; 56:867–874. [DOI] [PubMed] [Google Scholar]
- 244.Tardiff JC, Hewett TE, Palmer BM, Olsson C, Factor SM, Moore RL, Robbins J, Leinwand LA. Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. J Clin Invest 1999; 104:469–481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 245.McConnell BK, Jones KA, Fatkin D, Arroyo LH, Lee RT, Aristizabal O, Turnbull DH, Georgakopoulos D, Kass D, Bond M, Niimura H, Schoen FJ, Conner D, Fischman DA, Seidman CE, Seidman JG. Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice. J Clin Invest 1999; 104:1235–1244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 246.Meng Q, Bhandary B, Bhuiyan MS, James J, Osinska H, Valiente-Alandi I, Shay-Winkler K, Gulick J, Molkentin JD, Blaxall BC, Robbins J. Myofibroblast-Specific TGFbeta Receptor II Signaling in the Fibrotic Response to Cardiac Myosin Binding Protein C-Induced Cardiomyopathy. Circ Res 2018; 123:1285–1297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 247.Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, Kim JB, Schmitt JP, Molkentin JD, Norris RA, Tager AM, Hoffman SR, Markwald RR, Seidman CE, Seidman JG. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-beta. J Clin Invest 2010; 120:3520–3529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 248.Fornes P, Ratel S, Lecomte D. Pathology of arrhythmogenic right ventricular cardiomyopathy/dysplasia--an autopsy study of 20 forensic cases. J Forensic Sci 1998; 43:777–783. [PubMed] [Google Scholar]
- 249.Burke AP, Farb A, Tashko G, Virmani R. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases? Circulation 1998; 97:1571–1580. [DOI] [PubMed] [Google Scholar]
- 250.Hamilton RM. Arrhythmogenic right ventricular cardiomyopathy. Pacing Clin Electrophysiol 2009; 32 Suppl 2:S44–51. [DOI] [PubMed] [Google Scholar]
- 251.Tandri H, Saranathan M, Rodriguez ER, Martinez C, Bomma C, Nasir K, Rosen B, Lima JA, Calkins H, Bluemke DA. Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging. J Am Coll Cardiol 2005; 45:98–103. [DOI] [PubMed] [Google Scholar]
- 252.Yang Z, Bowles NE, Scherer SE, Taylor MD, Kearney DL, Ge S, Nadvoretskiy VV, DeFreitas G, Carabello B, Brandon LI, Godsel LM, Green KJ, Saffitz JE, Li H, Danieli GA, Calkins H, Marcus F, Towbin JA. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Res 2006; 99:646–655. [DOI] [PubMed] [Google Scholar]
- 253.Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004; 36:1162–1164. [DOI] [PubMed] [Google Scholar]
- 254.Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 2006; 113:1171–1179. [DOI] [PubMed] [Google Scholar]
- 255.Lombardi R, Chen SN, Ruggiero A, Gurha P, Czernuszewicz GZ, Willerson JT, Marian AJ. Cardiac Fibro-Adipocyte Progenitors Express Desmosome Proteins and Preferentially Differentiate to Adipocytes Upon Deletion of the Desmoplakin Gene. Circ Res 2016; 119:41–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 256.Lombardi R, Dong J, Rodriguez G, Bell A, Leung TK, Schwartz RJ, Willerson JT, Brugada R, Marian AJ. Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy. Circ Res 2009; 104:1076–1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 257.Dubash AD, Kam CY, Aguado BA, Patel DM, Delmar M, Shea LD, Green KJ. Plakophilin-2 loss promotes TGF-beta1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes. J Cell Biol 2016; 212:425–438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 258.Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 2000; 102:2700–2706. [DOI] [PubMed] [Google Scholar]
- 259.Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 2014; 11:255–265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 260.Bujak M, Kweon HJ, Chatila K, Li N, Taffet G, Frangogiannis NG. Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J Am Coll Cardiol 2008; 51:1384–1392. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 261.Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, Slater R, Palmer BM, Van Buren P, Meyer M, Redfield MM, Bull DA, Granzier HL, LeWinter MM. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 2015; 131:1247–1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 262.Trippel TD, Van Linthout S, Westermann D, Lindhorst R, Sandek A, Ernst S, Bobenko A, Kasner M, Spillmann F, Gonzalez A, Lopez B, Ravassa S, Pieske B, Paulus WJ, Diez J, Edelmann F, Tschope C. Investigating a biomarker-driven approach to target collagen turnover in diabetic heart failure with preserved ejection fraction patients. Effect of torasemide versus furosemide on serum C-terminal propeptide of procollagen type I (DROP-PIP trial). Eur J Heart Fail 2018; 20:460–470. [DOI] [PubMed] [Google Scholar]
- 263.Yahalom-Ronen Y, Rajchman D, Sarig R, Geiger B, Tzahor E. Reduced matrix rigidity promotes neonatal cardiomyocyte dedifferentiation, proliferation and clonal expansion. Elife 2015; 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 264.Qiu Y, Bayomy AF, Gomez MV, Bauer M, Du P, Yang Y, Zhang X, Liao R. A role for matrix stiffness in the regulation of cardiac side population cell function. Am J Physiol Heart Circ Physiol 2015; 308:H990–997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 265.Sanchez-Iranzo H, Galardi-Castilla M, Sanz-Morejon A, Gonzalez-Rosa JM, Costa R, Ernst A, Sainz de Aja J, Langa X, Mercader N. Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart. Proc Natl Acad Sci U S A 2018; 115:4188–4193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 266.Wang J, Karra R, Dickson AL, Poss KD. Fibronectin is deposited by injury-activated epicardial cells and is necessary for zebrafish heart regeneration. Dev Biol 2013; 382:427–435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 267.Bassat E, Mutlak YE, Genzelinakh A, Shadrin IY, Baruch Umansky K, Yifa O, Kain D, Rajchman D, Leach J, Riabov Bassat D, Udi Y, Sarig R, Sagi I, Martin JF, Bursac N, Cohen S, Tzahor E. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 2017; 547:179–184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 268.Kuhn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, Keating MT. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med 2007; 13:962–969. [DOI] [PubMed] [Google Scholar]
- 269.Lorts A, Schwanekamp JA, Elrod JW, Sargent MA, Molkentin JD. Genetic manipulation of periostin expression in the heart does not affect myocyte content, cell cycle activity, or cardiac repair. Circ Res 2009; 104:e1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 270.Morikawa Y, Zhang M, Heallen T, Leach J, Tao G, Xiao Y, Bai Y, Li W, Willerson JT, Martin JF. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci Signal 2015; 8:ra41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 271.Leach JP, Heallen T, Zhang M, Rahmani M, Morikawa Y, Hill MC, Segura A, Willerson JT, Martin JF. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 2017; 550:260–264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 272.Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 2008; 14:213–221. [DOI] [PubMed] [Google Scholar]
- 273.Sanchez PL, Fernandez-Santos ME, Costanza S, Climent AM, Moscoso I, Gonzalez-Nicolas MA, Sanz-Ruiz R, Rodriguez H, Kren SM, Garrido G, Escalante JL, Bermejo J, Elizaga J, Menarguez J, Yotti R, Perez del Villar C, Espinosa MA, Guillem MS, Willerson JT, Bernad A, Matesanz R, Taylor DA, Fernandez-Aviles F. Acellular human heart matrix: A critical step toward whole heart grafts. Biomaterials 2015; 61:279–289. [DOI] [PubMed] [Google Scholar]
- 274.Taylor DA, Frazier OH, Elgalad A, Hochman-Mendez C, Sampaio LC. Building a Total Bioartificial Heart: Harnessing Nature to Overcome the Current Hurdles. Artif Organs 2018; 42:970–982. [DOI] [PubMed] [Google Scholar]
- 275.Guyette JP, Charest JM, Mills RW, Jank BJ, Moser PT, Gilpin SE, Gershlak JR, Okamoto T, Gonzalez G, Milan DJ, Gaudette GR, Ott HC. Bioengineering Human Myocardium on Native Extracellular Matrix. Circ Res 2016; 118:56–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 276.Weis SM, Emery JL, Becker KD, McBride DJ Jr., Omens JH, McCulloch AD. Myocardial mechanics and collagen structure in the osteogenesis imperfecta murine (oim). Circ Res 2000; 87:663–669. [DOI] [PubMed] [Google Scholar]
- 277.Robert V, Van Thiem N, Cheav SL, Mouas C, Swynghedauw B, Delcayre C. Increased cardiac types I and III collagen mRNAs in aldosterone-salt hypertension. Hypertension 1994; 24:30–36. [DOI] [PubMed] [Google Scholar]
- 278.Wei S, Chow LT, Shum IO, Qin L, Sanderson JE. Left and right ventricular collagen type I/III ratios and remodeling post-myocardial infarction. J Card Fail 1999; 5:117–126. [DOI] [PubMed] [Google Scholar]
- 279.Inoue K, Kusachi S, Niiya K, Kajikawa Y, Tsuji T. Sequential changes in the distribution of type I and III collagens in the infarct zone: immunohistochemical study of experimental myocardial infarction in the rat. Coron Artery Dis 1995; 6:153–158. [DOI] [PubMed] [Google Scholar]
- 280.Marijianowski MM, Teeling P, Mann J, Becker AE. Dilated cardiomyopathy is associated with an increase in the type I/type III collagen ratio: a quantitative assessment. J Am Coll Cardiol 1995; 25:1263–1272. [DOI] [PubMed] [Google Scholar]
- 281.Pauschinger M, Doerner A, Remppis A, Tannhauser R, Kuhl U, Schultheiss HP. Differential myocardial abundance of collagen type I and type III mRNA in dilated cardiomyopathy: effects of myocardial inflammation. Cardiovasc Res 1998; 37:123–129. [DOI] [PubMed] [Google Scholar]
- 282.Marijianowski MM, van der Loos CM, Mohrschladt MF, Becker AE. The neonatal heart has a relatively high content of total collagen and type I collagen, a condition that may explain the less compliant state. J Am Coll Cardiol 1994; 23:1204–1208. [DOI] [PubMed] [Google Scholar]
- 283.Mays PK, Bishop JE, Laurent GJ. Age-related changes in the proportion of types I and III collagen. Mech Ageing Dev 1988; 45:203–212. [DOI] [PubMed] [Google Scholar]
- 284.Medugorac I Characterization of intramuscular collagen in mammalian left ventricle. Basic Res Cardiol 1982; 77:589–598. [DOI] [PubMed] [Google Scholar]
- 285.Tan G, Shim W, Gu Y, Qian L, Chung YY, Lim SY, Yong P, Sim E, Wong P. Differential effect of myocardial matrix and integrins on cardiac differentiation of human mesenchymal stem cells. Differentiation 2010; 79:260–271. [DOI] [PubMed] [Google Scholar]
- 286.Lincoln J, Florer JB, Deutsch GH, Wenstrup RJ, Yutzey KE. ColVa1 and ColXIa1 are required for myocardial morphogenesis and heart valve development. Dev Dyn 2006; 235:3295–3305. [DOI] [PubMed] [Google Scholar]
- 287.Honda M, Goto Y, Kuzuo H, Ishikawa S, Morioka S, Yamori Y, Moriyama K. Biochemical remodeling of collagen in the heart of spontaneously hypertensive rats--prominent increase in type V collagen. Jpn Circ J 1993; 57:434–441. [DOI] [PubMed] [Google Scholar]
- 288.Sant’Ana PG, Batah SS, Leao PS, Teodoro WR, de Souza SLB, Ferreira Mota GA, Vileigas DF, da Silva VL, de Campos DHS, Okoshi K, Capelozzi VL, Cicogna AC, Fabro AT. Heart remodeling produced by aortic stenosis promotes cardiomyocyte apoptosis mediated by collagen V imbalance. Pathophysiology 2018; 25:373–379. [DOI] [PubMed] [Google Scholar]
- 289.Nath DS, Tiriveedhi V, Basha HI, Phelan D, Moazami N, Ewald GA, Mohanakumar T. A role for antibodies to human leukocyte antigens, collagen-V, and K-alpha1-Tubulin in antibody-mediated rejection and cardiac allograft vasculopathy. Transplantation 2011; 91:1036–1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 290.Koch M, Laub F, Zhou P, Hahn RA, Tanaka S, Burgeson RE, Gerecke DR, Ramirez F, Gordon MK. Collagen XXIV, a vertebrate fibrillar collagen with structural features of invertebrate collagens: selective expression in developing cornea and bone. J Biol Chem 2003; 278:43236–43244. [DOI] [PubMed] [Google Scholar]
- 291.Wang W, Olson D, Liang G, Franceschi RT, Li C, Wang B, Wang SS, Yang S. Collagen XXIV (Col24alpha1) promotes osteoblastic differentiation and mineralization through TGF-beta/Smads signaling pathway. Int J Biol Sci 2012; 8:1310–1322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 292.Plumb DA, Dhir V, Mironov A, Ferrara L, Poulsom R, Kadler KE, Thornton DJ, Briggs MD, Boot-Handford RP. Collagen XXVII is developmentally regulated and forms thin fibrillar structures distinct from those of classical vertebrate fibrillar collagens. J Biol Chem 2007; 282:12791–12795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 293.Eghbali M, Blumenfeld OO, Seifter S, Buttrick PM, Leinwand LA, Robinson TF, Zern MA, Giambrone MA. Localization of types I, III and IV collagen mRNAs in rat heart cells by in situ hybridization. J Mol Cell Cardiol 1989; 21:103–113. [DOI] [PubMed] [Google Scholar]
- 294.Imoto K, Hirakawa M, Okada M, Yamawaki H. Canstatin modulates L-type calcium channel activity in rat ventricular cardiomyocytes. Biochem Biophys Res Commun 2018; 499:954–959. [DOI] [PubMed] [Google Scholar]
- 295.Lencova-Popelova O, Jirkovsky E, Mazurova Y, Lenco J, Adamcova M, Simunek T, Gersl V, Sterba M. Molecular remodeling of left and right ventricular myocardium in chronic anthracycline cardiotoxicity and post-treatment follow up. PLoS One 2014; 9:e96055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 296.Watanabe T, Kusachi S, Yamanishi A, Kumashiro H, Nunoyama H, Sano I, Nakahama M, Murakami T, Naito I, Ninomiya Y, Tsuji T. Localization of type IV collagen alpha chain in the myocardium of dilated and hypertrophic cardiomyopathy. Jpn Heart J 1998; 39:753–762. [DOI] [PubMed] [Google Scholar]
- 297.de Castro Bras LE, Toba H, Baicu CF, Zile MR, Weintraub ST, Lindsey ML, Bradshaw AD. Age and SPARC change the extracellular matrix composition of the left ventricle. Biomed Res Int 2014; 2014:810562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 298.Doi K, Sawada F, Toda G, Yamachika S, Seto S, Urata Y, Ihara Y, Sakata N, Taniguchi N, Kondo T, Yano K. Alteration of antioxidants during the progression of heart disease in streptozotocin-induced diabetic rats. Free Radic Res 2001; 34:251–261. [DOI] [PubMed] [Google Scholar]
- 299.Okada M, Morioka S, Kanazawa H, Yamawaki H. Canstatin inhibits isoproterenol-induced apoptosis through preserving mitochondrial morphology in differentiated H9c2 cardiomyoblasts. Apoptosis 2016; 21:887–895. [DOI] [PubMed] [Google Scholar]
- 300.Yamanishi A, Kusachi S, Nakahama M, Ninomiya Y, Watanabe T, Kumashiro H, Nunoyama H, Kondo J, Naito I, Tsuji T. Sequential changes in the localization of the type IV collagen alpha chain in the infarct zone: immunohistochemical study of experimental myocardial infarction in the rat. Pathol Res Pract 1998; 194:413–422. [DOI] [PubMed] [Google Scholar]
- 301.Iruela-Arispe ML, Sage EH. Expression of type VIII collagen during morphogenesis of the chicken and mouse heart. Dev Biol 1991; 144:107–118. [DOI] [PubMed] [Google Scholar]
- 302.Skrbic B, Bjornstad JL, Marstein HS, Carlson CR, Sjaastad I, Nygard S, Bjornstad S, Christensen G, Tonnessen T. Differential regulation of extracellular matrix constituents in myocardial remodeling with and without heart failure following pressure overload. Matrix Biol 2013; 32:133–142. [DOI] [PubMed] [Google Scholar]
- 303.Akahori H, Tsujino T, Naito Y, Sawada H, Sugahara M, Fukui M, Ohyanagi M, Mitsuno M, Miyamoto Y, Masuyama T. Nuclear factor-kappaB-hypoxia-inducible factor-2 pathway in aortic valve stenosis. J Heart Valve Dis 2014; 23:558–566. [PubMed] [Google Scholar]
- 304.Rahkonen O, Savontaus M, Abdelwahid E, Vuorio E, Jokinen E. Expression patterns of cartilage collagens and Sox9 during mouse heart development. Histochem Cell Biol 2003; 120:103–110. [DOI] [PubMed] [Google Scholar]
- 305.Marro J, Pfefferli C, de Preux Charles AS, Bise T, Jazwinska A. Collagen XII Contributes to Epicardial and Connective Tissues in the Zebrafish Heart during Ontogenesis and Regeneration. PLoS One 2016; 11:e0165497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 306.Dharmavaram RM, Huynh AI, Jimenez SA. Characterization of human chondrocyte and fibroblast type XII collagen cDNAs. Matrix Biol 1998; 16:343–348. [DOI] [PubMed] [Google Scholar]
- 307.Tao G, Levay AK, Peacock JD, Huk DJ, Both SN, Purcell NH, Pinto JR, Galantowicz ML, Koch M, Lucchesi PA, Birk DE, Lincoln J. Collagen XIV is important for growth and structural integrity of the myocardium. J Mol Cell Cardiol 2012; 53:626–638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 308.Lai CH, Chu ML. Tissue distribution and developmental expression of type XVI collagen in the mouse. Tissue Cell 1996; 28:155–164. [DOI] [PubMed] [Google Scholar]
- 309.Fitzgerald J, Bateman JF. A new FACIT of the collagen family: COL21A1. FEBS Lett 2001; 505:275–280. [DOI] [PubMed] [Google Scholar]
- 310.Koch M, Schulze J, Hansen U, Ashwodt T, Keene DR, Brunken WJ, Burgeson RE, Bruckner P, Bruckner-Tuderman L. A novel marker of tissue junctions, collagen XXII. Journal of Biological Chemistry 2004; 279:22514–22521. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 311.Hagg P, Vaisanen T, Tuomisto A, Rehn M, Tu H, Huhtala P, Eskelinen S, Pihlajaniemi T. Type XIII collagen: a novel cell adhesion component present in a range of cell-matrix adhesions and in the intercalated discs between cardiac muscle cells. Matrix Biol 2001; 19:727–742. [DOI] [PubMed] [Google Scholar]
- 312.Sund M, Ylonen R, Tuomisto A, Sormunen R, Tahkola J, Kvist AP, Kontusaari S, Autio-Harmainen H, Pihlajaniemi T. Abnormal adherence junctions in the heart and reduced angiogenesis in transgenic mice overexpressing mutant type XIII collagen. EMBO J 2001; 20:5153–5164. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 313.Tahkola J, Rasanen J, Sund M, Makikallio K, Autio-Harmainen H, Pihlajaniemi T. Cardiac dysfunction in transgenic mouse fetuses overexpressing shortened type XIII collagen. Cell Tissue Res 2008; 333:61–69. [DOI] [PubMed] [Google Scholar]
- 314.Kondo J, Kusachi S, Ninomiya Y, Yoshioka H, Oohashi T, Doi M, Murakami T, Moritani H, Kumashiro H, Tsuji T. Expression of type XVII collagen alpha 1 chain mRNA in the mouse heart. Jpn Heart J 1998; 39:211–220. [DOI] [PubMed] [Google Scholar]
- 315.Koch M, Veit G, Stricker S, Bhatt P, Kutsch S, Zhou P, Reinders E, Hahn RA, Song R, Burgeson RE, Gerecke DR, Mundlos S, Gordon MK. Expression of type XXIII collagen mRNA and protein. J Biol Chem 2006; 281:21546–21557. [DOI] [PubMed] [Google Scholar]
- 316.Tanaka T, Wakabayashi T, Oizumi H, Nishio S, Sato T, Harada A, Fujii D, Matsuo Y, Hashimoto T, Iwatsubo T. CLAC-P/collagen type XXV is required for the intramuscular innervation of motoneurons during neuromuscular development. J Neurosci 2014; 34:1370–1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 317.Sidwell RU, Yates R, Atherton D. Dilated cardiomyopathy in dystrophic epidermolysis bullosa. Arch Dis Child 2000; 83:59–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 318.Ryan TD, Ware SM, Lucky AW, Towbin JA, Jefferies JL, Hinton RB. Left ventricular noncompaction cardiomyopathy and aortopathy in a patient with recessive dystrophic epidermolysis bullosa. Circ Heart Fail 2012; 5:e81–82. [DOI] [PubMed] [Google Scholar]
- 319.Klewer SE, Krob SL, Kolker SJ, Kitten GT. Expression of type VI collagen in the developing mouse heart. Dev Dyn 1998; 211:248–255. [DOI] [PubMed] [Google Scholar]
- 320.Crossman DJ, Shen X, Jullig M, Munro M, Hou Y, Middleditch M, Shrestha D, Li A, Lal S, Dos Remedios CG, Baddeley D, Ruygrok PN, Soeller C. Increased collagen within the transverse tubules in human heart failure. Cardiovasc Res 2017; 113:879–891. [DOI] [PubMed] [Google Scholar]
- 321.Bonaldo P, Braghetta P, Zanetti M, Piccolo S, Volpin D, Bressan GM. Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet 1998; 7:2135–2140. [DOI] [PubMed] [Google Scholar]
- 322.van der Kooi AJ, de Voogt WG, Bertini E, Merlini L, Talim FB, Ben Yaou R, Urtziberea A, de Visser M. Cardiac and pulmonary investigations in Bethlem myopathy. Arch Neurol 2006; 63:1617–1621. [DOI] [PubMed] [Google Scholar]
- 323.Spiro MJ, Crowley TJ. Increased rat myocardial type VI collagen in diabetes mellitus and hypertension. Diabetologia 1993; 36:93–98. [DOI] [PubMed] [Google Scholar]
- 324.Mollnau H, Munkel B, Schaper J. Collagen VI in the extracellular matrix of normal and failing human myocardium. Herz 1995; 20:89–94. [PubMed] [Google Scholar]
- 325.Veit G, Kobbe B, Keene DR, Paulsson M, Koch M, Wagener R. Collagen XXVIII, a novel von Willebrand factor A domain-containing protein with many imperfections in the collagenous domain. J Biol Chem 2006; 281:3494–3504. [DOI] [PubMed] [Google Scholar]
- 326.Hagg PM, Hagg PO, Peltonen S, Autio-Harmainen H, Pihlajaniemi T. Location of type XV collagen in human tissues and its accumulation in the interstitial matrix of the fibrotic kidney. Am J Pathol 1997; 150:2075–2086. [PMC free article] [PubMed] [Google Scholar]
- 327.Kivirikko S, Saarela J, Myers JC, Autio-Harmainen H, Pihlajaniemi T. Distribution of type XV collagen transcripts in human tissue and their production by muscle cells and fibroblasts. Am J Pathol 1995; 147:1500–1509. [PMC free article] [PubMed] [Google Scholar]
- 328.Rasi K, Piuhola J, Czabanka M, Sormunen R, Ilves M, Leskinen H, Rysa J, Kerkela R, Janmey P, Heljasvaara R, Peuhkurinen K, Vuolteenaho O, Ruskoaho H, Vajkoczy P, Pihlajaniemi T, Eklund L. Collagen XV is necessary for modeling of the extracellular matrix and its deficiency predisposes to cardiomyopathy. Circ Res 2010; 107:1241–1252. [DOI] [PubMed] [Google Scholar]
- 329.Eklund L, Piuhola J, Komulainen J, Sormunen R, Ongvarrasopone C, Fassler R, Muona A, Ilves M, Ruskoaho H, Takala TE, Pihlajaniemi T. Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice. Proc Natl Acad Sci U S A 2001; 98:1194–1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 330.Carvalhaes LS, Gervasio OL, Guatimosim C, Heljasvaara R, Sormunen R, Pihlajaniemi T, Kitten GT. Collagen XVIII/endostatin is associated with the epithelial-mesenchymal transformation in the atrioventricular valves during cardiac development. Dev Dyn 2006; 235:132–142. [DOI] [PubMed] [Google Scholar]
- 331.Saarela J, Ylikarppa R, Rehn M, Purmonen S, Pihlajaniemi T. Complete primary structure of two variant forms of human type XVIII collagen and tissue-specific differences in the expression of the corresponding transcripts. Matrix Biol 1998; 16:319–328. [DOI] [PubMed] [Google Scholar]
- 332.Utriainen A, Sormunen R, Kettunen M, Carvalhaes LS, Sajanti E, Eklund L, Kauppinen R, Kitten GT, Pihlajaniemi T. Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line. Hum Mol Genet 2004; 13:2089–2099. [DOI] [PubMed] [Google Scholar]
- 333.Gouya G, Siller-Matula JM, Fritzer-Szekeres M, Neuhold S, Storka A, Neuhofer LM, Clodi M, Hulsmann M, Pacher R, Wolzt M. Association of endostatin with mortality in patients with chronic heart failure. Eur J Clin Invest 2014; 44:125–135. [DOI] [PubMed] [Google Scholar]
- 334.Lauten A, Majos E, Muhlich A, Wahlers T, Weider S, Fischer JH, Figulla HR, Bloch W. Ischemia-reperfusion injury activates early extracellular matrix processing and expression of endostatin in the heart with differential effects of temperature. Basic Res Cardiol 2009; 104:559–569. [DOI] [PubMed] [Google Scholar]
- 335.Panchal VR, Rehman J, Nguyen AT, Brown JW, Turrentine MW, Mahomed Y, March KL. Reduced pericardial levels of endostatin correlate with collateral development in patients with ischemic heart disease. J Am Coll Cardiol 2004; 43:1383–1387. [DOI] [PubMed] [Google Scholar]
- 336.Isobe K, Kuba K, Maejima Y, Suzuki J, Kubota S, Isobe M. Inhibition of endostatin/collagen XVIII deteriorates left ventricular remodeling and heart failure in rat myocardial infarction model. Circ J 2010; 74:109–119. [DOI] [PubMed] [Google Scholar]
- 337.Belmadani S, Bernal J, Wei CC, Pallero MA, Dell’italia L, Murphy-Ullrich JE, Berecek KH. A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II. Am J Pathol 2007; 171:777–789. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 338.Sharifi-Sanjani M, Shoushtari AH, Quiroz M, Baust J, Sestito SF, Mosher M, Ross M, McTiernan CF, St Croix CM, Bilonick RA, Champion HC, Isenberg JS. Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3. J Am Heart Assoc 2014; 3:e000670. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 339.Isenberg JS, Qin Y, Maxhimer JB, Sipes JM, Despres D, Schnermann J, Frazier WA, Roberts DD. Thrombospondin-1 and CD47 regulate blood pressure and cardiac responses to vasoactive stress. Matrix Biol 2009; 28:110–119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 340.Schroen B, Heymans S, Sharma U, Blankesteijn WM, Pokharel S, Cleutjens JP, Porter JG, Evelo CT, Duisters R, van Leeuwen RE, Janssen BJ, Debets JJ, Smits JF, Daemen MJ, Crijns HJ, Bornstein P, Pinto YM. Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy. Circ Res 2004; 95:515–522. [DOI] [PubMed] [Google Scholar]
- 341.Hanatani S, Izumiya Y, Takashio S, Kimura Y, Araki S, Rokutanda T, Tsujita K, Yamamoto E, Tanaka T, Yamamuro M, Kojima S, Tayama S, Kaikita K, Hokimoto S, Ogawa H. Circulating thrombospondin-2 reflects disease severity and predicts outcome of heart failure with reduced ejection fraction. Circ J 2014; 78:903–910. [DOI] [PubMed] [Google Scholar]
- 342.Papageorgiou AP, Swinnen M, Vanhoutte D, VandenDriessche T, Chuah M, Lindner D, Verhesen W, de Vries B, D’Hooge J, Lutgens E, Westermann D, Carmeliet P, Heymans S. Thrombospondin-2 prevents cardiac injury and dysfunction in viral myocarditis through the activation of regulatory T-cells. Cardiovasc Res 2012; 94:115–124. [DOI] [PubMed] [Google Scholar]
- 343.van Almen GC, Swinnen M, Carai P, Verhesen W, Cleutjens JP, D’Hooge J, Verheyen FK, Pinto YM, Schroen B, Carmeliet P, Heymans S. Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy. J Mol Cell Cardiol 2011; 51:318–328. [DOI] [PubMed] [Google Scholar]
- 344.Mustonen E, Aro J, Puhakka J, Ilves M, Soini Y, Leskinen H, Ruskoaho H, Rysa J. Thrombospondin-4 expression is rapidly upregulated by cardiac overload. Biochem Biophys Res Commun 2008; 373:186–191. [DOI] [PubMed] [Google Scholar]
- 345.Palao T, Rippe C, van Veen H, VanBavel E, Sward K, Bakker EN. Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms. Am J Physiol Heart Circ Physiol 2016; 310:H1486–1493. [DOI] [PubMed] [Google Scholar]
- 346.Sawaki D, Hou L, Tomida S, Sun J, Zhan H, Aizawa K, Son BK, Kariya T, Takimoto E, Otsu K, Conway SJ, Manabe I, Komuro I, Friedman SL, Nagai R, Suzuki T. Modulation of cardiac fibrosis by Kruppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes. Cardiovasc Res 2015; 107:420–430. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 347.Sato M, Toyozaki T, Odaka K, Uehara T, Arano Y, Hasegawa H, Yoshida K, Imanaka-Yoshida K, Yoshida T, Hiroe M, Tadokoro H, Irie T, Tanada S, Komuro I. Detection of experimental autoimmune myocarditis in rats by 111In monoclonal antibody specific for tenascin-C. Circulation 2002; 106:1397–1402. [DOI] [PubMed] [Google Scholar]
- 348.Yamamoto K, Dang QN, Kennedy SP, Osathanondh R, Kelly RA, Lee RT. Induction of tenascin-C in cardiac myocytes by mechanical deformation. Role of reactive oxygen species. J Biol Chem 1999; 274:21840–21846. [DOI] [PubMed] [Google Scholar]
- 349.Terasaki F, Okamoto H, Onishi K, Sato A, Shimomura H, Tsukada B, Imanaka-Yoshida K, Hiroe M, Yoshida T, Kitaura Y, Kitabatake A, Study Group for Intractable Diseases by a Grant from the Ministry of Health L, Welfare of J. Higher serum tenascin-C levels reflect the severity of heart failure, left ventricular dysfunction and remodeling in patients with dilated cardiomyopathy. Circ J 2007; 71:327–330. [DOI] [PubMed] [Google Scholar]
- 350.Yokokawa T, Sugano Y, Nakayama T, Nagai T, Matsuyama TA, Ohta-Ogo K, Ikeda Y, Ishibashi-Ueda H, Nakatani T, Yasuda S, Takeishi Y, Ogawa H, Anzai T. Significance of myocardial tenascin-C expression in left ventricular remodelling and long-term outcome in patients with dilated cardiomyopathy. Eur J Heart Fail 2016; 18:375–385. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 351.Podesser BK, Kreibich M, Dzilic E, Santer D, Forster L, Trojanek S, Abraham D, Krssak M, Klein KU, Tretter EV, Kaun C, Wojta J, Kapeller B, Goncalves IF, Trescher K, Kiss A. Tenascin-C promotes chronic pressure overload-induced cardiac dysfunction, hypertrophy and myocardial fibrosis. J Hypertens 2018; 36:847–856. [DOI] [PubMed] [Google Scholar]
- 352.Imanaka-Yoshida K, Hiroe M, Nishikawa T, Ishiyama S, Shimojo T, Ohta Y, Sakakura T, Yoshida T. Tenascin-C modulates adhesion of cardiomyocytes to extracellular matrix during tissue remodeling after myocardial infarction. Lab Invest 2001; 81:1015–1024. [DOI] [PubMed] [Google Scholar]
- 353.Willems IE, Arends JW, Daemen MJ. Tenascin and fibronectin expression in healing human myocardial scars. J Pathol 1996; 179:321–325. [DOI] [PubMed] [Google Scholar]
- 354.Kimura T, Tajiri K, Sato A, Sakai S, Wang Z, Yoshida T, Uede T, Hiroe M, Aonuma K, Ieda M, Imanaka-Yoshida K. Tenascin-C Accelerates Adverse Ventricular Remodeling after Myocardial Infarction by Modulating Macrophage Polarization. Cardiovasc Res 2018. [DOI] [PubMed]
- 355.Tamaoki M, Imanaka-Yoshida K, Yokoyama K, Nishioka T, Inada H, Hiroe M, Sakakura T, Yoshida T. Tenascin-C regulates recruitment of myofibroblasts during tissue repair after myocardial injury. Am J Pathol 2005; 167:71–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 356.Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X, Lafyatis R, Lee J, Hinchcliff M, Feghali-Bostwick C, Lakota K, Budinger GR, Raparia K, Tamaki Z, Varga J. Tenascin-C drives persistence of organ fibrosis. Nature communications 2016; 7:11703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 357.Bradshaw AD, Baicu CF, Rentz TJ, Van Laer AO, Bonnema DD, Zile MR. Age-dependent alterations in fibrillar collagen content and myocardial diastolic function: role of SPARC in post-synthetic procollagen processing. Am J Physiol Heart Circ Physiol 2010; 298:H614–622. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 358.Horn MA, Graham HK, Richards MA, Clarke JD, Greensmith DJ, Briston SJ, Hall MC, Dibb KM, Trafford AW. Age-related divergent remodeling of the cardiac extracellular matrix in heart failure: collagen accumulation in the young and loss in the aged. J Mol Cell Cardiol 2012; 53:82–90. [DOI] [PubMed] [Google Scholar]
- 359.Vanhoutte D, van Almen GC, Van Aelst LN, Van Cleemput J, Droogne W, Jin Y, Van de Werf F, Carmeliet P, Vanhaecke J, Papageorgiou AP, Heymans S. Matricellular proteins and matrix metalloproteinases mark the inflammatory and fibrotic response in human cardiac allograft rejection. Eur Heart J 2013; 34:1930–1941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 360.Rienks M, Carai P, van Teeffelen J, Eskens B, Verhesen W, Hemmeryckx B, Johnson DM, van Leeuwen R, Jones EA, Heymans S, Papageorgiou AP. SPARC preserves endothelial glycocalyx integrity, and protects against adverse cardiac inflammation and injury during viral myocarditis. Matrix Biol 2018; 74:21–34. [DOI] [PubMed] [Google Scholar]
- 361.Komatsubara I, Murakami T, Kusachi S, Nakamura K, Hirohata S, Hayashi J, Takemoto S, Suezawa C, Ninomiya Y, Shiratori Y. Spatially and temporally different expression of osteonectin and osteopontin in the infarct zone of experimentally induced myocardial infarction in rats. Cardiovasc Pathol 2003; 12:186–194. [DOI] [PubMed] [Google Scholar]
- 362.Singh K, Sirokman G, Communal C, Robinson KG, Conrad CH, Brooks WW, Bing OH, Colucci WS. Myocardial osteopontin expression coincides with the development of heart failure. Hypertension 1999; 33:663–670. [DOI] [PubMed] [Google Scholar]
- 363.Yu Q, Vazquez R, Khojeini EV, Patel C, Venkataramani R, Larson DF. IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. Am J Physiol Heart Circ Physiol 2009; 297:H76–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 364.Subramanian V, Krishnamurthy P, Singh K, Singh M. Lack of osteopontin improves cardiac function in streptozotocin-induced diabetic mice. Am J Physiol Heart Circ Physiol 2007; 292:H673–683. [DOI] [PubMed] [Google Scholar]
- 365.Dahiya S, Givvimani S, Bhatnagar S, Qipshidze N, Tyagi SC, Kumar A. Osteopontin-stimulated expression of matrix metalloproteinase-9 causes cardiomyopathy in the mdx model of Duchenne muscular dystrophy. J Immunol 2011; 187:2723–2731. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 366.Sakamuri SS, Takawale A, Basu R, Fedak PW, Freed D, Sergi C, Oudit GY, Kassiri Z. Differential impact of mechanical unloading on structural and nonstructural components of the extracellular matrix in advanced human heart failure. Transl Res 2016; 172:30–44. [DOI] [PubMed] [Google Scholar]
- 367.Graf K, Do YS, Ashizawa N, Meehan WP, Giachelli CM, Marboe CC, Fleck E, Hsueh WA. Myocardial osteopontin expression is associated with left ventricular hypertrophy. Circulation 1997; 96:3063–3071. [DOI] [PubMed] [Google Scholar]
- 368.Nakayama H, Nagai H, Matsumoto K, Oguro R, Sugimoto K, Kamide K, Ohishi M, Katsuya T, Okamoto H, Maeda M, Komamura K, Azuma J, Rakugi H, Fujio Y. Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population. Hypertens Res 2011; 34:1141–1146. [DOI] [PubMed] [Google Scholar]
- 369.Collins AR, Schnee J, Wang W, Kim S, Fishbein MC, Bruemmer D, Law RE, Nicholas S, Ross RS, Hsueh WA. Osteopontin modulates angiotensin II-induced fibrosis in the intact murine heart. J Am Coll Cardiol 2004; 43:1698–1705. [DOI] [PubMed] [Google Scholar]
- 370.Sam F, Xie Z, Ooi H, Kerstetter DL, Colucci WS, Singh M, Singh K. Mice lacking osteopontin exhibit increased left ventricular dilation and reduced fibrosis after aldosterone infusion. Am J Hypertens 2004; 17:188–193. [DOI] [PubMed] [Google Scholar]
- 371.Li J, Yousefi K, Ding W, Singh J, Shehadeh LA. Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure. Cardiovasc Res 2017; 113:633–643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 372.Matsui Y, Jia N, Okamoto H, Kon S, Onozuka H, Akino M, Liu L, Morimoto J, Rittling SR, Denhardt D, Kitabatake A, Uede T. Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy. Hypertension 2004; 43:1195–1201. [DOI] [PubMed] [Google Scholar]
- 373.Sawaki D, Czibik G, Pini M, Ternacle J, Suffee N, Mercedes R, Marcelin G, Surenaud M, Marcos E, Gual P, Clement K, Hue S, Adnot S, Hatem SN, Tsuchimochi I, Yoshimitsu T, Henegar C, Derumeaux G. Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production. Circulation 2018; 138:809–822. [DOI] [PubMed] [Google Scholar]
- 374.Caballero EP, Santamaria MH, Corral RS. Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease. Biochim Biophys Acta Mol Basis Dis 2018; 1864:11–23. [DOI] [PubMed] [Google Scholar]
- 375.Szalay G, Sauter M, Haberland M, Zuegel U, Steinmeyer A, Kandolf R, Klingel K. Osteopontin: a fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host. Circ Res 2009; 104:851–859. [DOI] [PubMed] [Google Scholar]
- 376.Abel B, Kurrer M, Shamshiev A, Marty RR, Eriksson U, Gunthert U, Kopf M. The osteopontin - CD44 pathway is superfluous for the development of autoimmune myocarditis. Eur J Immunol 2006; 36:494–499. [DOI] [PubMed] [Google Scholar]
- 377.Murry CE, Giachelli CM, Schwartz SM, Vracko R. Macrophages express osteopontin during repair of myocardial necrosis. Am J Pathol 1994; 145:1450–1462. [PMC free article] [PubMed] [Google Scholar]
- 378.Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T, Michael LH, Rollins BJ, Entman ML, Frangogiannis NG. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res 2005; 96:881–889. [DOI] [PubMed] [Google Scholar]
- 379.Shirakawa K, Endo J, Kataoka M, Katsumata Y, Yoshida N, Yamamoto T, Isobe S, Moriyama H, Goto S, Kitakata H, Hiraide T, Fukuda K, Sano M. IL (Interleukin)-10-STAT3-Galectin-3 Axis Is Essential for Osteopontin-Producing Reparative Macrophage Polarization After Myocardial Infarction. Circulation 2018; 138:2021–2035. [DOI] [PubMed] [Google Scholar]
- 380.Trueblood NA, Xie Z, Communal C, Sam F, Ngoy S, Liaw L, Jenkins AW, Wang J, Sawyer DB, Bing OH, Apstein CS, Colucci WS, Singh K. Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin. Circ Res 2001; 88:1080–1087. [DOI] [PubMed] [Google Scholar]
- 381.Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA. Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest 1996; 98:2218–2227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 382.Lenga Y, Koh A, Perera AS, McCulloch CA, Sodek J, Zohar R. Osteopontin expression is required for myofibroblast differentiation. Circ Res 2008; 102:319–327. [DOI] [PubMed] [Google Scholar]
- 383.Psarras S, Mavroidis M, Sanoudou D, Davos CH, Xanthou G, Varela AE, Panoutsakopoulou V, Capetanaki Y. Regulation of adverse remodelling by osteopontin in a genetic heart failure model. Eur Heart J 2012; 33:1954–1963. [DOI] [PubMed] [Google Scholar]
- 384.Renault MA, Robbesyn F, Reant P, Douin V, Daret D, Allieres C, Belloc I, Couffinhal T, Arnal JF, Klingel K, Desgranges C, Dos Santos P, Charpentier F, Gadeau AP. Osteopontin expression in cardiomyocytes induces dilated cardiomyopathy. Circ Heart Fail 2010; 3:431–439. [DOI] [PubMed] [Google Scholar]
- 385.Dalal S, Zha Q, Daniels CR, Steagall RJ, Joyner WL, Gadeau AP, Singh M, Singh K. Osteopontin stimulates apoptosis in adult cardiac myocytes via the involvement of CD44 receptors, mitochondrial death pathway, and endoplasmic reticulum stress. Am J Physiol Heart Circ Physiol 2014; 306:H1182–1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 386.Wu H, Chen L, Xie J, Li R, Li GN, Chen QH, Zhang XL, Kang LN, Xu B. Periostin expression induced by oxidative stress contributes to myocardial fibrosis in a rat model of high salt-induced hypertension. Mol Med Rep 2016; 14:776–782. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 387.Katsuragi N, Morishita R, Nakamura N, Ochiai T, Taniyama Y, Hasegawa Y, Kawashima K, Kaneda Y, Ogihara T, Sugimura K. Periostin as a novel factor responsible for ventricular dilation. Circulation 2004; 110:1806–1813. [DOI] [PubMed] [Google Scholar]
- 388.Wang D, Oparil S, Feng JA, Li P, Perry G, Chen LB, Dai M, John SW, Chen YF. Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Hypertension 2003; 42:88–95. [DOI] [PubMed] [Google Scholar]
- 389.Chiao YA, Ramirez TA, Zamilpa R, Okoronkwo SM, Dai Q, Zhang J, Jin YF, Lindsey ML. Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovasc Res 2012; 96:444–455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 390.Melenovsky V, Benes J, Skaroupkova P, Sedmera D, Strnad H, Kolar M, Vlcek C, Petrak J, Benes J Jr., Papousek F, Oliyarnyk O, Kazdova L, Cervenka L. Metabolic characterization of volume overload heart failure due to aorto-caval fistula in rats. Mol Cell Biochem 2011; 354:83–96. [DOI] [PubMed] [Google Scholar]
- 391.Pohjolainen V, Rysa J, Napankangas J, Koobi P, Eraranta A, Ilves M, Serpi R, Porsti I, Ruskoaho H. Left ventricular periostin gene expression is associated with fibrogenesis in experimental renal insufficiency. Nephrol Dial Transplant 2012; 27:115–122. [DOI] [PubMed] [Google Scholar]
- 392.Stansfield WE, Andersen NM, Tang RH, Selzman CH. Periostin is a novel factor in cardiac remodeling after experimental and clinical unloading of the failing heart. Ann Thorac Surg 2009; 88:1916–1921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 393.Kong P, Christia P, Saxena A, Su Y, Frangogiannis NG. Lack of specificity of Fibroblast Specific Protein (FSP)1 in cardiac remodeling and fibrosis. Am J Physiol Heart Circ Physiol 2013. [DOI] [PMC free article] [PubMed]
- 394.Chen Z, Xie J, Hao H, Lin H, Wang L, Zhang Y, Chen L, Cao S, Huang X, Liao W, Bin J, Liao Y. Ablation of periostin inhibits post-infarction myocardial regeneration in neonatal mice mediated by the phosphatidylinositol 3 kinase/glycogen synthase kinase 3beta/cyclin D1 signalling pathway. Cardiovasc Res 2017; 113:620–632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 395.Taniyama Y, Katsuragi N, Sanada F, Azuma J, Iekushi K, Koibuchi N, Okayama K, Ikeda-Iwabu Y, Muratsu J, Otsu R, Rakugi H, Morishita R. Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction. Hypertension 2016; 67:356–361. [DOI] [PubMed] [Google Scholar]
- 396.Snider P, Hinton RB, Moreno-Rodriguez RA, Wang J, Rogers R, Lindsley A, Li F, Ingram DA, Menick D, Field L, Firulli AB, Molkentin JD, Markwald R, Conway SJ. Periostin is required for maturation and extracellular matrix stabilization of noncardiomyocyte lineages of the heart. Circ Res 2008; 102:752–760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 397.Norris RA, Damon B, Mironov V, Kasyanov V, Ramamurthi A, Moreno-Rodriguez R, Trusk T, Potts JD, Goodwin RL, Davis J, Hoffman S, Wen X, Sugi Y, Kern CB, Mjaatvedt CH, Turner DK, Oka T, Conway SJ, Molkentin JD, Forgacs G, Markwald RR. Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues. J Cell Biochem 2007; 101:695–711. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 398.Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, Muller SJ, Fahy JV. Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A 2010; 107:14170–14175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 399.Hakuno D, Kimura N, Yoshioka M, Mukai M, Kimura T, Okada Y, Yozu R, Shukunami C, Hiraki Y, Kudo A, Ogawa S, Fukuda K. Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents. J Clin Invest 2010; 120:2292–2306. [DOI] [PMC free article] [PubMed] [Google Scholar]