title: Growth differentiation factor 5 regulates cardiac repair after myocardial infarction.
abstract: OBJECTIVE
  The aim of this study was to examine the function of the bone morphogenic protein growth differentiation factor 5 (Gdf5) in a mouse model of myocardial infarction (MI).
  
  
  BACKGROUND
  The Gdf5 has been implicated in skeletal development, but a potential role in the heart had not been studied.
  
  
  METHODS
  The Gdf5-knockout (KO) and wild-type (WT) mice were subjected to permanent left anterior descending coronary artery (LAD) ligation. Cardiac pathology, function, gene expression levels, and signaling pathways downstream of Gdf5 were examined. Effects of recombinant Gdf5 (rGdf5) were tested in primary cardiac cell cultures.
  
  
  RESULTS
  The WT mice showed increased cardiac Gdf5 levels after MI, with increased expression in peri-infarct cardiomyocytes and myofibroblasts. At 1 and 7 days after MI, no differences were observed in ischemic or infarct areas between WT and Gdf5-KO mice. However, by 28 days after MI, Gdf5-KO mice exhibited increased infarct scar expansion and thinning with decreased arteriolar density compared with WT. The Gdf5-KO hearts also displayed increased left ventricular dilation, with decreased contractility after MI. At 4 days after MI, Gdf5-KO mice exhibited increased cardiomyocyte apoptosis and decreased expression of anti-apoptotic genes Bcl2 and Bcl-xL compared with WT. Unexpectedly, Gdf5-KO hearts displayed increased Smad 1/5/8 phosphorylation but decreased p38-mitogen-activated protein kinase (MAPK) phosphorylation versus WT. The latter was associated with increased collagen gene (Col1a1, Col3a1) expression and fibrosis. In cultures, rGdf5 induced p38-MAPK phosphorylation in cardiac fibroblasts and Smad-dependent increases in Bcl2 and Bcl-xL in cardiomyocytes.
  
  
  CONCLUSIONS
  Increased expression of Gdf5 after MI limits infarct scar expansion in vivo. These effects might be mediated by Gdf5-induced p38-MAPK signaling in fibroblasts and Gdf5-driven Smad-dependent pro-survival signaling in cardiomyocytes.
authors.affiliation: Division of Cardiology, University Health Network, Toronto, Ontario, Canada. syed.zaidi@uhnres.utoronto.ca
authors.forename: Syed H E
authors.initials: SH
authors.lastname: Zaidi
authors.forename: Qingling
authors.initials: Q
authors.lastname: Huang
authors.forename: Abdul
authors.initials: A
authors.lastname: Momen
authors.forename: Ali
authors.initials: A
authors.lastname: Riazi
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
mesh_terms: D000818:Animals; D017209:Apoptosis; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects; D055428:Growth Differentiation Factor 5 / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C525894:Gdf5 protein, mouse; D055428:Growth Differentiation Factor 5; D011994:Recombinant Proteins; D051896:Smad Proteins, Receptor-Regulated; D048051:p38 Mitogen-Activated Protein Kinases