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. Author manuscript; available in PMC: 2014 Dec 1.
Published in final edited form as: Biochim Biophys Acta. 2013 Sep 17;1832(12):2271–2276. doi: 10.1016/j.bbadis.2013.09.004

Cardiac matrix: a clue for future therapy

Paras Kumar Mishra 1,*, Srikanth Givvimani 2,*, Vishalakshi Chavali 1, Suresh C Tyagi 2
PMCID: PMC4111554  NIHMSID: NIHMS525550  PMID: 24055000

Abstract

Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium-myocyte (E-M) coupling and contractility of cardiomyocytes. The Matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by E-M coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases.

Keywords: Heart, VEGF, MMP, TIMP, miRNA, stem cell, angiogenesis, cardiovascular diseases

Introduction

Although heart is a unique and dynamic organ functioning ceaselessly throughout life, it is highly vulnerable to disease pathology. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality across the world. Although majority of research emphasize on CVD, less attention has been paid to the sophisticated regulatory mechanisms and micro-environment provided by cardiac matrix. Cardiac matrix is crucial for synchronized beating of cardiomyocytes that maintain the untiring contraction-relaxation cycle of the heart. Recently, it was discovered that elasticity of matrix plays a pivotal role in lineage specification [1] and self-renewal [2] of stem cells. The heart has self-renewing capacity due to endogenous cardiac stem cells [3]. It was reported that during cardiac stem cell therapy, paracrine effect causing inhibition of cardiac fibrosis, apoptosis and enhanced contractility [4], could be a possible factor mediated by matrix modulation. Another report using a cocktail of prosurvival miRNA-21, -24 and -221 was shown to enhance the engraftment and viability of transplanted cardiac progenitor cells [5] corroborating the fact that synergism of miRNA and stem cell could be a better therapeutic approach in heart failure [6]. We have demonstrated that targeted deletion of MMP-9 induces miRNAs that are down regulated in failing hearts and improves contractility and calcium handling by up regulating SERCA2 in cardiomyocytes [7]. Additionally, induction of MMP-9 and attenuation of TIMP-4 contribute to cardiac fibrosis in diabetic hearts whereas ablation of MMP-9 decreases cardiac fibrosis and increases cardiac stem cells (CPCs) in the heart [8, 9]. However, the cross-talk between MMP-9, miRNA and stem cells is unclear. The understanding of complex interactions among MMPs, miRNA and CPC in the milieu of cardiac matrix can be exploited for regeneration and improvement of myocardial contractility. In this review, the plausible mechanism of structural and functional remodeling of cardiac matrix in the context of heart failure and future therapeutic approaches is elaborated.

Matrix metalloproteinases as key players in cardiac matrix remodeling

MMPs are zinc containing calcium-dependent endopeptidases which are released as inactive zymogens in a latent form [10, 11] and are activated by auto-proteolysis, serine proteases, or other activated MMPs [10]. Pathological cardiac remodeling can be triggered by pressure (hypertension) or volume overload, hyperhomocysteinemia, and/or activation of renin-angiotensin-aldosterone system mediated oxidative/redox stress that alters the levels of different MMPs and TIMPs and signaling molecules leading to heart failure (Figure 1). Cardiac remodeling includes degradation of extracellular matrix (ECM), myocyte hypertrophy, impaired angiogenesis, collateralization, changes in receptor signaling cascade, fibrosis, autophagy, apoptosis, impaired differentiation and survival of CSC, fetal gene reprogramming, differential expressions of miRNAs and epigenetic modifications. Although MMPs are involved in cardiovascular remodeling, they have a distinct spatial and temporal role. The temporal activation of MMP and TIMP has been elucidated in myocardial infarction. While MMP-2 induction was observed on day1 and peaked at two weeks post-MI, TIMP-4 induction and activation remained the same from day1 [12]. Similarly, MMP-9 but not MMP-2 was activated in end-stage heart failure [13]. The spatial translocation of MMP-9 into mitochondria is associated with arrhythmia and cardiomyocyte contractility dysfunction [14, 15]. MMP-2 is constitutively expressed [16-18], whereas MMP-9 is inducible and instigates pathophysiological remodeling [7, 9, 19]. Although transgenic expression of MMP-2 impairs myocardial contractility [20], the disruption of myocardial filament by MMP-2 may not be true. The induction of MMP-2 may have an effect on other MMPs. For example in diabetics, MMP-2 is attenuated but MMP-9 shows robust activation[9] resulting in contractile dysfunction [7]. MMP-2 is reported to be up regulated in human aortic atherosclerotic lesions [21]. In heart failure, the level of MMP-2 increases during compensatory stage but during de-compensatory stage MMP-9 supersedes the levels of MMP-2 resulting in failure [16]. Recently, the existence of a novel intracellular MMP-2 isoform was reported in the mitochondria. This isoform is (65 kDA) induced by oxidative stress and has been shown to play an important role in promoting cardiac hypertrophy, apoptosis and systolic failure [22]. Despite the pathological role described above, further studies are required to confirm these findings. The vascular MMP versus cardiac MMP is interesting in the sense that the remodeling outcome may be compensatory in cardiac matrix while it is detrimental in the arterial pathology. Accumulation of collagen and loss of elastin the arterial wall correlate with decreased arterial compliance in hypertension and aging. Enhanced extracellular matrix remodeling in the arterial wall affects the course of disease pathology in atherosclerosis [23]. Plaque disruption due to vascular remodeling mostly results in thrombotic occlusion [24].

Figure 1.

Figure 1

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Pressure and/volume overload, diabetes, homocysteine and renin-angiotensin- aldosterone system (RAAS) engendered oxidative stress that activates latent MMPs and imbalances MMP/TIMP axis (remodeling). This generates angiogenic and anti-angiogenic factors, leading to compensatory to de-compensatory congestive heart failure (CHF).

MMPs are inhibited by tissue inhibitor of metalloproteinases (TIMPs). There are four types of TIMPs: TIMP-1, -2, -3 and -4. TIMPs are implicated in cardiac fibrosis [25], angiogenesis [26, 27], and apoptosis [28, 29]. Cardiac enriched TIMP-4 plays an important role in matrix remodeling by inhibition of MMP-9 activity [30]. An imbalance of MMP/TIMP has been implicated in structural and functional changes in hypertensive heart disease [31]. The pathological role of MMPs in left ventricular remodeling and heart failure has been extensively reported in both pre-clinical and clinical studies [32]. In spontaneously hypertensive rats, MMP inhibition was shown to attenuate pathological cardiac remodeling during hypertension [33]. In a recent study, MMP-2 activity was found to be responsible for the development of left ventricular hypertrophy in a two kidney, one clip hypertensive rat model [34]. In the same model, temporal changes in MMP-2 activity was associated with simultaneous cardiac remodeling along with increased expression of TGF-β and reactive oxygen species (ROS) [35]. Treatment with antioxidant, Tempol alleviated the cardiac remodeling by decreasing the TGF-β and MMPs expression [35]. Although significant role of MMP-2 in remodeling has been extensively reported, recent report suggests that the infusion of recombinant human MMP-2 in lambs did not alter any hemodynamic parameters but for the impairment of beta adrenoceptor activation response [36].

The involvement of MMPs in left ventricular pathology has been extensively reported [37] however, a recent study in acute pulmonary thromboembolism (APT) showed a similar role in right ventricular remodeling [38]. In APT, ROS production was associated with MMP activation and treatment with non-specific MMP inhibitors or antioxidants were found to mitigate MMP induced remodeling [39, 40].

MMP inhibitors

MMP inhibitors are classified as specific and non-specific inhibitors. Non-specific inhibitors act through chelation of Zn2+ ion [41]. Nonspecific inhibitors such as batimastat, marimastat, GM-6001 (ilomastat or gelardin), PD-166793 and ONO-4817 [42] have been extensively used in various experimental models of disease. Lately, though peptides containing the HWGF motif, CRRHWGFEFC and CTTHWGFTLC, were found to be selective inhibitors of MMP-9 and MMP-2 [41], their clinical usage is highly questionable because of their susceptibility to proteolysis inside the body. Tetracyclines are a group of antibiotics that are found to have MMP inhibition property. Chemically modified tetracyclines (CMTs) are devoid of antimicrobial property but retain the MMP inhibition function [43]. CMT 3 has been shown to inhibit MMP-2 and -9 activities along with collagenase activity and ameliorate pathological cardiovascular remodeling. This is the only CMT administered to humans in clinical trials [44].

Cross-talk between MMPs and miRNAs in cardiac matrix

Cardiac matrix is implicated in conferring biochemical stability of growth factors, facilitating signal transduction and inducing apoptosis [23]. Since MMPs degrade cardiac matrix, they also disrupt the endothelial–myocyte coupling, signaling cascade and regulatory machinery necessary for maintaining normal function [9]. MicroRNAs (miRNAs) are small (20-23 nucleotide long), non-coding RNAs that regulate gene expression either by mRNA degradation or translational repression [45, 46]. Nearly 2000 miRNAs have been reported in humans. MicroRNAs play a pivotal role in the regulation of cardiovascular diseases [6, 47]. MMPs also alter the expression of miRNAs. The first report of regulation of miRNAs by MMPs was documented in MMP-9KO hearts [7]. This study revealed several key miRNAs that are down regulated in the failing heart, are up regulated in the MMP-9KO hearts [7]. However, the mechanism of miRNA regulation by MMPs is still not clear. Nevertheless, this finding opens a new avenue to explore the complex regulatory network between MMPs and miRNAs and dissect the mechanism of cardiac matrix remodeling in pathological conditions.

Cardiac ECM, MMPs, miRNAs and epigenetic modifications

ECM is the key component of the myocardium which not only maintains the structural integrity and plasticity of the heart but also provides the micro-environment for signaling cascade required for cardiac homeostasis [48]. Collagen provides stiffness to ECM and is involved in structural remodeling leading to heart failure [8, 9, 48-50]. Collagen is a substrate for both MMP-2 and MMP-9 [10]. MMP-9 is found to be robust and degraded ECM in a failing heart [51-53]. Targeted deletion of MMP-9 mitigated fibrosis in diabetic hearts [8]. During the remodeling process, though both collagen and elastin are resynthesized as a compensatory mechanism, collagen turnover is faster than elastin and contributes to cardiac fibrosis. The cardiac fibrosis impairs endothelium-cardiomyocyte (E-C) coupling leading to ventricular dysfunction [9]. The role of MMP-9 on contractility of the heart was elucidated by an ex-vivo experiment, in which treatment with MMP-9 decreases rate of contraction and relaxation (±dL/dt) of cardiomyocytes and inhibition of MMP-9 by tissue inhibitor of metalloproteinase-4 (TIMP4) ameliorated impaired contractility [7]. The targeted deletion of MMP-9 also improved contractility of cardiomyocytes at in vivo studies [7].

Micro RNA-133 is attenuated in heart failure. Inhibition of miR-133 induced cardiac hypertrophy [54] while transgenic expression of miR-133 attenuated cardiac fibrosis in trans-aortic constriction model of heart failure [55]. Interestingly, targeted deletion of MMP-9 up-regulated the expression of miR-133 in a failing heart [7]. Recently, it was reported that abrogation of miR-133 induces DNA methyl transferases (DNMTs) and over expression of miR-133 inhibits DNMTs in cardiomyocytes [56]. Surprisingly, up-regulation of miR-133 down regulates hyperglycemia mediated induction of DNMTs (DNMT-1) suggesting a crucial role of miR-133 in epigenetic modification in diabetic hearts [56]. Although ablation of MMP-9 induces miR-133, the underlying mechanism is unclear. The plausible mechanism of MMP-9 mediated amelioration of heart failure could be that the deletion of MMP-9 gene provides a favorable cardiac matrix micro-environment required for increased transcription of specific miRNAs that mitigates cardiac dysfunction. Further understanding of cross-talk between ECM, MMPs and miRNAs will open a new avenue to elucidate the complex regulatory network in the heart that can be exploited for therapeutic endeavor.

Elasticity of cardiac matrix and stem cell survival and differentiation

Stem cells are recognized by three salient properties, (i) self-renewal, (ii) pluripotent, and (iii) clonogenic [57]. The human heart is a self-renewing organ [3] because of its endogenous cardiac stem cells and self-renewal is dependent on the elasticity of the surrounding matrix [1, 2]. The ECM elasticity determines stem cell lineage specification, expansion and differentiation [1, 8]. In the heart, ECM exhibits all the mechanical properties and provides a frame work required for differentiation of cardiac stem cells [58]. The contractility of cardiomyocytes also depends on the elasticity of matrix [2]. It is documented that embryonic cardiomyocytes beat best on a matrix with heart like elasticity [2]. As MMP-9 deletion contributes to the elasticity of ECM and up regulates several miRNAs involved in stem cell differentiation, we determined the role of MMP-9 in the survival and differentiation of cardiac stem cells [8]. The comparative analysis of c-kit (a stem cell marker) and troponin I (cardiomyocytes marker) in the WT, diabetic Ins2+/- Akita and Ins2+/- /MMP-9-/- (diabetic mice without MMP-9 gene) revealed that MMP-9 deletion enhances stem cell survival and differentiation to cardiomyocytes in the heart [8]. It points to a complex interaction amongst MMPs (at least MMP-9), ECM elasticity and miRNAs that determines the cardiac stem cell survival and differentiation. ECM might be crucial for regulating stem cell differentiation signaling in autocrine and paracrine fashion for regenerating the myocardium that is pivotal in stem cell therapy (Figure 2).

Figure 2.

Figure 2

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Activation of MMP-9 increases ECM turn over, attenuates miRNAs, induces cardiac stem cell apoptosis and inhibits their differentiation leading to pathological cardiac remodeling.

MMPs, angiogenesis, cardiovascular remodeling and repair

Aberrant remodeling in the myocardial ECM results in heart failure. MMPs play a pivotal role in regulation of angiogenesis by altering the balance between angiogenic and anti-angiogenic factors [16, 59, 60]. Brooks and colleagues reported that an angiogenic stimulus induces vascular remodeling and defines the role of MMP-2 and integrin (αvβ3) [61, 62]. During hypertrophic remodeling and angiogenesis, MMP-2 is constitutively expressed [16, 49]. Alternatively, MMP-9 is expressed in the failing heart and induces the expression of anti-angiogenic factors - endostatin and angiostatin [16, 50, 63]. Previous reports demonstrated that the therapeutic angiogenesis using growth promoting factors can increase blood supply to the ischemic myocardium [64-66].

Studies in cardiac specific inducible protein kinase B (AKT1) transgenic mice show decreased angiogenesis during pathological remodeling and suggested that both heart size and cardiac function are angiogenesis dependent. Additionally, the disruption of coordinated cardiac hypertrophy and angiogenesis plays a crucial role in the pathogenesis of heart failure [67]. Although role of MMPs in acute coronary syndrome (ACS) is documented [23, 24], the inhibition of vascular versus cardiac MMP is counter intuitive. The comparative analyses of angiostatin, endostatin and coronary collateral formation in myocardial tissue harvested from diabetic and non-diabetic coronary artery disease (CAD) patients revealed that angiostatin and endostatin are induced in diabetic CAD patients compared with non-diabetic patients and negatively correlates with coronary collateralization [63]. Although MMPs are integral regulators of angiogenesis and anti-angiogenesis, whether all MMPs have similar or differential function is nebulous. MMP-2 and MMP-9 are mostly studied MMPs in angiogenesis; however contrasting roles have been reported. We and several others believe that MMP-2 is pro-angiogenic but MMP-9 is anti-angiogenic in the heart [16, 63, 68]. The role of MMP-9 as anti-angiogenic factor is also supported by the finding that abrogation of MMP-9 attenuates cardiac hypertrophy and collagen accumulation in the heart after myocardial infarction [69]. It is documented that endothelial mesenchymal transition (EndMT) similar to that of epithelial mesenchymal transition (EMT) plays an important role in synthesizing new fibroblasts resulting in increased deposition of fibrosis in endocardium and microvascular endothelium [70-72]. However, ablation of MMP-9 gene inhibits EMT [71, 73]. These findings points to the role of MMP-9 as inducer of EndMT in cardiac and vascular endothelium that promotes cardiac fibrosis along with increased expression of anti-angiogenic factors such as angiostatin and endostatin in an experimental ascending aortic banding model (Figure 3).

Figure 3.

Figure 3

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Mechanism of pressure overload (ascending aortic banding) mediated compensatory cardiac hypertrophy to de-compensatory heart failure. During early stages of aortic banding, angiogenesis is increased due to up-regulation of MMP-2, vascular endothelial growth factor (VEGF) and inhibition of MMP-9. However, sustained overload results in de-compensatory heart failure due to anti-angiogenesis, where expression of MMP-9 supersedes that of MMP-2 and promotes release of anti-angiogenic factors such as angiostatin, endostatin and parstatin. MMP-9 also stimulate endothelial mesenchymal transition (EndMT) leading to fibrosis and end stage heart failure.

Imbalance of angiogenesis and anti-angiogenesis could be one of the major pathogenic mechanisms during cardiac injury such as pressure overload, ischemia and infarction. Restoration of angiogenesis may potentiate myocardial recovery from an insult or injury. We and others have reported that therapeutic doses of hydrogen sulfide (H2S) promote angiogenesis and have cardio protective role in pressure overload models [68, 74, 75]. Since homocysteine is a precursor for H2S, the treatment with H2S can mitigate hyperhomocysteinemia mediated cardiac toxicity. Although angiogenic therapy for the cardiac repair is promising, successful clinical data is still missing and targeted induction of angiogenesis in the localized area of heart could be a viable approach for cardiac repair. Empirical studies revealed that administration of self-assembling peptide nanofiber combined with VEGF in the post myocardial infarction heart stabilized VEGF locally for more than 14 days and improved angiogenesis, arteriogenesis and cardiac performance [76]. This study upholds the cardiac angiogenesis therapy for future clinical trials. However, understanding the types of VEGF and their functions in relation to cardiac repair is crucial as different VEGFs are involved in vasculogenesis, angiogenesis and lymphangiogenesis (Figure 4).

Figure 4.

Figure 4

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The effect of different vascular endothelial growth factors (VEGF) following their binding to corresponding receptors (VEGFR). VEGF1 and 2 up regulates vasculogenesis and angiogenesis through Flt -1and Flk-1/KDR pathway, whereas VEGF3 enhances lymphangiogenesis through Flt-4 pathway.

Exploiting cardiac matrix for future therapy

Cardiac matrix contains MMPs, TIMPs, miRNAs, DNMTs, cardiac stem cells, angiogenic and anti-angiogenic factors, signaling molecules involved in autophagy, apoptosis, epigenetic modifications, fibrosis and hypertrophy. The unique interactions of these factors in the favorable cardiac matrix milieu maintain synchronized beating of cardiomyocytes and contractility of the heart. However, differential expression of even a single molecule disrupts the sophisticated regulatory network by altering the matrix milieu that leads to pathological remodeling. For example, inhibition of only miR-133 causes cardiac hypertrophy [54]. Similarly, ablation of MMP-9 reduces cardiac fibrosis [8]. In the diabetic heart, miR-133 is attenuated that induces DNA methylation [56] but MMP-9 is up regulated that contributes to cardiac fibrosis [9]. Attenuation of miR-133 is also responsible for cardiac fibrosis [55]. Therefore, the interactions of miR-133, MMP-9, epigenetic modifications and cardiac fibrosis are somehow closely related. Similarly, stem cell function is regulated by miRNAs [5] and MMP-9 regulates stem cell survival [8] and miRNA levels [7]. Therefore, CSC survival, differentiation and function depend on interactions of miRNAs and MMP-9. As elucidated above, there are empirical evidences suggesting the role of MMP-9 and MMP-2 in angiogenesis, which is a promising area for therapy of cardiovascular diseases. The interactions of these factors constitute the dynamic cardiac matrix. There is very little known about how the dynamic cardiac matrix behaves during myocardial regeneration, pathological cardiac remodeling and compensatory and de-compensatory stages of heart failure. The detailed insights of signaling cascade of apoptosis, autophagy, epigenetic modifications and angiogenesis by cardiac matrix in the failing heart and their regulation by miRNAs, MMPs and TIMPs will provide a clue for future therapy for heart failure (Figure 5).

Figure 5.

Figure 5

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The unique cross –talk amongst MMP-9/TIMP4, miRNA, epigenetic modification, fibrosis, hypertrophy, cardiac stem cell proliferation and differentiation, growth factors, autophagy and apoptosis is maintained in the cardiac matrix. The interactions of these molecules alter in pathological remodeling due to change in matrix milieu. Dissecting the causative factor (s) and their interactions will provide a clue to for future therapy.

Highlights.

  • MMPs and TIMPs in Cardiac matrix.

  • MMP-9 regulates differential expression of Micro RNAs.

  • Cardiac matrix regulating cardiac disease pathology.

Acknowledgments

The financial supports from American Heart Association grant (11BGIA 7690055) and National Institute of Health, HL-113281 to P.K.M. and HL-108621 and HL-74185 to S.C.T. is gratefully acknowledged.

Abbreviations

CVD

cardiovascular disease

CSC

cardiac stem cell

CPC

cardiac progenitor cell

miRNA

MicroRNA

MMP

matrix metalloproteinase

TIMP

tissue inhibitor of MMP

SERCA

sarco endoplasmic reticulum ca2+ATPase

ECM

extracellular matrix

ROS

reactive oxygen species

APT

acute pulmonary thromboembolism

DNMT

DNA methyl transferase

VEGF

vascular endothelial growth factor

Footnotes

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