Table 6.
Role of fibroblast activation and extracellular matrix remodeling in cardiac rupture
| Gene/Protein | Mechanism | Ref. |
|---|---|---|
| Hsp47 | Fibroblast-specific activation of Hsp47 was found to protect from cardiac rupture my promoting reparative myofibroblast activation. | (51) |
| TLR9 | TLR9 signaling protects from rupture by activating myofibroblasts possibly through an interaction with HMGB1. | (58) |
| Smad3 | Myofibroblast-specific Smad3, but not Smad2, signaling protects from late rupture post-MI by triggering an integrin-mediated response in myofibroblasts, thus contributing to formation of an organized scar. | (40, 52) |
| IL-35 | IL-35 protects from post-MI cardiac rupture promoting reparative macrophage responses and improving repair. | (46) |
| miR-144 | miR-144 was implicated in the pathogenesis of cardiac rupture, presumably through effects on ECM remodeling. | (35) |
| Mast cell protease 4 | Chymase mast cell protease 4 was implicated in post-MI cardiac rupture, presumably through effects on matrix remodeling. | (39) |
| Heme oxygenase-1 (Hmox1) | Mice deficient in Hmox1 had lower rates of post-MI cardiac rupture, with greater collagen type I production compared with wild-type mice. | (83) |
| Dectin-2 | Dectin-2 KO mice demonstrated lower post-MI cardiac rupture rates with increased expression of α-smooth muscle actin and collagen I/III and reduced MMP-2 and -9 expression. | (97) |
| miR-155 | mir-155-deficient mice exhibited lower rates of post-MI cardiac rupture, associated with more abundant myofibroblasts and a– increased collagen disposition in the infarct. | (92) |
| CD39 | CD39-deficient mice demonstrated lower post-MI cardiac rupture rates associated with elevated fibrin and collagen deposition and increased reparative macrophage influx to the infarcted area. | (82). |
| NEIL3 | Neil3−/− mice showed increased post-MI myocardial rupture, presumably through ECM dysregulation and increased levels of MMP-2. | (70) |
| TLR9 | TLR9 was suggested to reduce post-MI cardiac rupture rates presumably through proliferation and differentiation of cardiac fibroblasts. | (71) |
| Hand1 | Hand1+/− mice had decreased cardiac rupture rates associated with lower MMP-9 activity. | (59) |
| CD28 | CD28KO mice had higher post-MI cardiac rupture rates, lower collagen deposition, and lower myofibroblast numbers. | (54) |
| Twinkle | Twinkle overexpression reduced post-MI cardiac rupture rates presumably through suppression of MMP-2 and -9 in the border zone of the infarct. | (44) |
| Follistatin-like 1 | Conditional ablation of Fstl1 in S100a4-expressing fibroblast lineage cells was reported to reduce numbers of myofibroblast and expression of ECM proteins in the infarct, and demonstrated increased post-MI cardiac rupture. | (63) |
| Girdin | Girdin S1416A knock-in mice (in which the Akt phosphorylation site is replaced with alanin) had reduced cardiac myofibroblast proliferation and collagen deposition that was implicated in higher rates of post-MI cardiac rupture. | (34) |
| Sirtuin 7 | Sirt7−/− mice showed high susceptibility to cardiac rupture, associated with reduced myofibroblast differentiation and perturbed TGFβ responses. | (3) |
| Osteoglycin | Osteoglycin-null mice had significantly increased post-MI cardiac rupture rates. Tissue disruption and impaired collagen fibrilogenesis were implicated. | (88) |
| Phospholipase A2 receptor (PLA2R) | PLA2R-deficient mice exhibited higher rates of post-MI cardiac rupture, associated with decreased numbers of myofibroblasts and attenuated collagen deposition in the infarcted myocardium. PLA2R was implicated in migration and proliferation of myofibroblasts through interactions with integrin-β1. | (67) |
| Melusin | Melusin overexpression reduced post-MI cardiac rupture rates, increasing matricellular protein expression in the infarcted area. | (86) |
| MMP-28 | MMP-28 deletion increased post-MI cardiac rupture rates, presumably through impaired M2 macrophage activation and reduced deposition of ECM proteins. | (61) |
| Syndecan-4 | Syndecan-4 KO mice exhibited increased rates of post-MI cardiac rupture, associated with suppressed inflammation and impaired granulation tissue formation in the heart post-MI. | (64) |
| TIMP3 | TIMP3−/− mice exhibited increased rates of post-MI cardiac rupture presumably through increased MMP activity, activated EGFR signaling, decreased myofibroblast numbers, and collagen deposition. | (32), (49) |
| Bcrp1/Abcg2 | Bcrp1/Abcg2 KO mice exhibited higher post-MI cardiac rupture rates, with reduced capillary, myofibroblast, and macrophage densities in the peri-infarction area. | (37) |
| SPARC | SPARC-null mice exhibited increased rates of post-MI rupture, associated with disorganized granulation tissue formation and defective scar maturation. | (78) |
| Biglycan | Biglycan-deficient mice had higher post-MI rupture rates. Impaired collagen matrix organization was implicated. | (95) |
| Periostin | Periostin−/− mice had increased post-MI rupture rates, associated with lower numbers of myofibroblasts and impaired collagen fibril formation in the infarct. | (69, 79) |
| MMP-2 | MMP-2-null mice exhibited reduced post-MI cardiac rupture, presumably through reduced gelatinolytic activity, and attenuated ECM degradation. | (65) |
| Factor XIII | FXIII−/− mice had markedly higher post-MI cardiac rupture rates, associated with lower collagen I and higher MMP-9 levels. | (68) |
| Angiotensin II receptor (AT2R) | AT2R-null mice had increased post-MI rupture rates, associated with reduced collagen deposition in the infarct. | (42) |
| uPA, TIMP1 | uPA−/− mice exhibited low post-MI cardiac rupture rates. In addition, gene transfer of TIMP1 protected mice from rupture-related death. | (36) |
MI, myocardial infarction; KO, knockout; MMP, matrix metalloproteinase.