Growth Differentiation Factor 5 Regulates Cardiac Repair After Myocardial Infarction

• Published in: Journal of the American College of Cardiology Vol. 55; no. 2; pp. 135 - 143
• Main Authors: Zaidi, Syed H.E., PhD, Huang, Qingling, PhD, Momen, Abdul, MD, Riazi, Ali, PhD, Husain, Mansoor, MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 12.01.2010; Elsevier; Elsevier Limited
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiomyocytes; Cardiovascular; Cell culture; Cell Culture Techniques; collagen gene expression; Coronary heart disease; Deoxyribonucleic acid; Disease Models, Animal; DNA; Fibroblasts - drug effects; Gene expression; growth differentiation factor 5; Growth Differentiation Factor 5 - pharmacology; Growth Differentiation Factor 5 - physiology; Heart; Heart attacks; Heart rate; Internal Medicine; Kinases; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; mitogen-activated protein kinase; myocardial infarction; Myocardial Infarction - etiology; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - drug effects; p38 Mitogen-Activated Protein Kinases - metabolism; Polymerase chain reaction; Proteins; Recombinant Proteins - pharmacology; Rodents; Smad Proteins, Receptor-Regulated - metabolism; Statistical methods; Variance analysis; Ontario Canada; Canada; California; United States > US; growth differentiation factor 5; ribonucleic acid; RNA; myocardial infarction; smooth muscle; left anterior descending coronary artery; LV; mRNA; ribonucleic acid interference; mitogen-activated protein kinase; TUNEL; inhibitor of differentiation 1; rGdf5; recombinant growth differentiation factor 5; RT-PCR; messenger ribonucleic acid; SM; left ventricle/ventricular; MI; WT; extracellular signal regulated kinase; knockout; RNAi; KO; collagen gene expression; MAPK; Gdf5; LAD; MMP; anterior wall; reverse-transcriptase polymerase chain reaction; AW; terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling; ID1; matrix metalloproteinase; wild-type; ERK; Myocardial infarction; Corrective surgery; Regulation(control); Treatment; Cardiovascular disease; Circulatory system; Cardiology; Differentiation; Repair; Coronary heart disease; Myocardial disease; Growth factor
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2009.08.041

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.