Journal
CARDIOVASCULAR RESEARCH
Volume 100, Issue 1, Pages 84-94Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvt158
Keywords
Myocardial infarction; Cathepsin S; Myofibroblast; Fibronectin; Collagen; Trans-differentiation
Categories
Funding
- National Institutes of Health [HL60942, HL81090, HL88547, HL56985]
- EIA from the American Heart Association [0840118N]
- National Natural Science foundation of China [30670867]
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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. 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-1-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 functionurecapitulating the findings in mice treated with E64d. Along with its established activities in ECM degradation, CatS plays novel roles in TGF-1 signalling, myofibroblast trans-differentiation, and ECM protein synthesis, thereby regulating scar formation in the infarcted myocardium and preserving LV function after experimental MI.
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