Abstract 14287: The Matricellular Protein CCN2/CTGF Alters Remodeling and Fibrotic Response Following Myocardial Infarction in Mice
Myocardial infarction (MI) causes remodeling of the myocardium where fibrosis is an important response. Several secreted factors, including transforming growth factor (TGF)β, are shown to participate in the development of fibrosis. We have previously shown increased myocardial expression of CCN2 in postschemic remodeling of the heart, but it is not known how this may regulate the fibrotic response. The objective of this study is to investigate the role of CCN2 in development of remodeling and fibrosis following MI. MI was induced by ligation of the left coronary artery in transgenic mice with cardiac-restricted overexpression of CCN2 (Tg-CCN2) and compared with non-transgenic littermate control (NLC) mice. Animals were harvested after 28 days. Fibroblasts were isolated from NLC mice, maintained in culture (passage 1) and stimulated with recombinant CCN2 (250 nmol/L) and TGFβ-1 (0.5 µg/ml) for 48 hours. Following MI we observed that the increase in myocardial collagen contents were smaller in Tg-CCN2 mice than in NLC mice (3.2±0.4-fold vs. 5.8±0.5-fold, n=6, p<0.01). Tg-CCN2 mice also maintained higher LV fractional shortening (20.2±1.5% vs. 14.3±2.3%, n=12, p<0.05) and ejection fraction (40.7±2.7% vs. 29.2±4.4, n=12, p<0.05) and revealed less dilatation of LV end-diastolic inner diameter (5.1±0.1mm vs. 5.7±0.3mm, n=12, p<0.05). Finally, more Tg-CCN2 animals survived the study period (67% vs. 38%, p<0.05). In isolated fibroblasts, CCN2 reduced protein expression of the myofibroblast marker α-smooth muscle actin (SMA) to 44±5%, p<0.01 (n=3) of control values. CCN2 reduced stress fiber formation (α-SMA) in fibroblasts maintained in culture. Interestingly, CCN2 inhibited a TGFβ-1-induced differentiation of fibroblasts by preventing upregulation of α-SMA protein levels. We also observed CCN2 to inhibit TGFβ-1 induced stress fiber formation. We conclude that the remodeling process is attenuated and LV function improved in mice with cardiac-restricted overexpression of CCN2 following MI. These changes may be related to direct effects of CCN2 on fibroblasts in the myocardium. Our results also suggest that CCN2 diminishes effects of the pro-fibrotic responses of TGFβ-1.
- © 2012 by American Heart Association, Inc.