| First Author | Chen H | Year | 2013 |
| Journal | Cardiovasc Res | Volume | 100 |
| Issue | 1 | Pages | 84-94 |
| PubMed ID | 23771947 | Mgi Jnum | J:219475 |
| Mgi Id | MGI:5620872 | Doi | 10.1093/cvr/cvt158 |
| Citation | Chen H, et al. (2013) Cathepsin S-mediated fibroblast trans-differentiation contributes to left ventricular remodelling after myocardial infarction. Cardiovasc Res 100(1):84-94 |
| abstractText | BACKGROUND: Extracellular matrix (ECM) turnover plays an important role in left ventricular (LV) remodelling following myocardial infarction (MI). Cysteinyl cathepsins contribute to ECM catabolism in arterial diseases, suggesting their participation in post-MI remodelling. METHODS AND RESULTS: Left anterior descending artery ligation-induced MI in mice showed increased expression and activity of cathepsin S (CatS). Administration of a non-selective cathepsin inhibitor, E64d, aggravated LV dysfunction at 7 and 28 days post-MI. Mechanistic studies showed that E64d increased post-MI inflammatory cell accumulation and cytokine expression, but did not affect apoptosis or angiogenesis in infarcted myocardium. Furthermore, E64d suppressed TGF-beta1-induced Smad2 and Smad3 activation and expression of fibronectin extra domain A (ED-A), an alternatively spliced fibronectin variant, and subsequently prevented cardiac fibroblast trans-differentiation into myofibroblast, which contributed to post-MI collagen and fibronectin synthesis and deposition. Consistently, selective inhibition or genetically determined deficiency of CatS also reduced myocardial Smad2 and Smad3 activation and ED-A fibronectin expression, thus suppressing fibroblast trans-differentiation and resulting in adverse collagen turnover and impaired cardiac function-recapitulating the findings in mice treated with E64d. CONCLUSION: Along with its established activities in ECM degradation, CatS plays novel roles in TGF-beta1 signalling, myofibroblast trans-differentiation, and ECM protein synthesis, thereby regulating scar formation in the infarcted myocardium and preserving LV function after experimental MI. |
