Author + information
- Received May 11, 2009
- Revision received July 15, 2009
- Accepted August 3, 2009
- Published online January 12, 2010.
- Syed H.E. Zaidi, PhD*,†,§,* (, )
- Qingling Huang, PhD§,
- Abdul Momen, MD§,
- Ali Riazi, PhD‖ and
- Mansoor Husain, MD*,†,‡
- ↵*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
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.
- collagen gene expression
- growth differentiation factor 5
- mitogen-activated protein kinase
- myocardial infarction
This work was supported by grants from the Heart & Stroke Foundation of Ontario (HSFO)(NA5808) and Toronto General Hospital Foundation to Dr. Zaidi, and grants from the Canadian Institutes of Health Research(MOP117801) and HSFO(CI: 5503) to Dr. Husain.
- Received May 11, 2009.
- Revision received July 15, 2009.
- Accepted August 3, 2009.
- American College of Cardiology Foundation