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PRE-CLINICAL RESEARCH

Growth Differentiation Factor 5 Regulates Cardiac Repair After Myocardial Infarction

Syed H.E. Zaidi, PhD^_*,,,_*, Qingling Huang, PhD, Abdul Momen, MD, Ali Riazi, PhD^|| and Mansoor Husain, MD^_*,,

^_* Division of Cardiology, University Health Network, Toronto, Ontario, Canada
Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada
McEwen Centre for Regenerative Medicine, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
^|| Labatt Family Heart Centre, Hospital for Sick Children, Toronto, Ontario, Canada

Manuscript received May 11, 2009; revised manuscript received July 15, 2009, accepted August 3, 2009.

^_* Reprint requests and correspondence: Dr. Syed H. E. Zaidi, Division of Cardiology, Department of Medicine, University of Toronto and University Health Network, 101 College Street, TMDT East Tower, Room 3-910, Toronto, Ontario M5G 1L7, Canada (Email: syed.zaidi{at}uhnres.utoronto.ca).

Objectives: 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.

Key Words: collagen gene expression • growth differentiation factor 5 • mitogen-activated protein kinase • myocardial infarction

Abbreviations and Acronyms   AW = anterior wall   ERK = extracellular signal regulated kinase   Gdf5 = growth differentiation factor 5   ID1 = inhibitor of differentiation 1   LAD = left anterior descending coronary artery   LV = left ventricle/ventricular   MAPK = mitogen-activated protein kinase   MI = myocardial infarction   MMP = matrix metalloproteinase   mRNA = messenger ribonucleic acid   KO = knockout   rGdf5 = recombinant growth differentiation factor 5   RNA = ribonucleic acid   RNAi = ribonucleic acid interference   RT-PCR = reverse-transcriptase polymerase chain reaction   SM = smooth muscle   TUNEL = terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling   WT = wild-type

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