title: Cathepsin S-mediated fibroblast trans-differentiation contributes to left ventricular remodelling after myocardial infarction.
abstract: 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.
  
  
  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-β1-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.
  
  
  CONCLUSIONS
  Along with its established activities in ECM degradation, CatS plays novel roles in TGF-β1 signalling, myofibroblast trans-differentiation, and ECM protein synthesis, thereby regulating scar formation in the infarcted myocardium and preserving LV function after experimental MI.
authors.affiliation: Department of Cardiology, Cardiovascular Key Lab of Zhejiang Province, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Mei-Xiang
authors.initials: MX
authors.lastname: Xiang
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Aina
authors.initials: A
authors.lastname: He
authors.forename: Chun-Na
authors.initials: CN
authors.lastname: Jin
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Wang
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D002403:Cathepsins / Q000032:analysis / Q000502:physiology*; D054338:Cell Transdifferentiation; D003094:Collagen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology*; D058628:Myofibroblasts / Q000473:pathology*; D051899:Smad2 Protein / Q000502:physiology; D051900:Smad3 Protein / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000209:etiology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D000199:Actins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D003094:Collagen; D002403:Cathepsins; C028217:cathepsin S
keywords: Cathepsin S; Collagen; Fibronectin; Myocardial infarction; Myofibroblast; Trans-differentiation