Abstract 17341: The Matricellular Protein CCN2/CTGF Enhances Scar Healing After Myocardial Infarction and Inhibits TGFβ-Induced Myofibroblast Differentiation Limiting Myocardial Fibrosis
Adequate scar healing is critical after myocardial infarction (MI). However, prolonged activity of myofibroblasts may cause excessive myocardial fibrosis leading to impaired cardiac function. We have previously shown that myocardial expression of CCN2 is substantially increased in ischemic heart failure. Yet, the role of CCN2 in healing of MI and in regulation of myocardial fibrosis is still poorly understood. Thus, the objective of this study is to investigate the role of CCN2 in infarct healing and myocardial 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 in non-transgenic control (NTC) mice. Fibroblasts were isolated from NTC mice and stimulated with or without recombinant (r)CCN2 (250 nmol/L) and/or TGFβ-1 (2.5 μg/ml) after first passage. Area of necrosis 24 hours after induction of MI was similar in Tg-CCN2 and NTC mice. Deposition of collagen in the infarct region was higher and increased more rapidly in Tg-CCN2 mice than in NTC mice (day 5 post-MI collagen content NTC 16.6 ± 0.8 vs Tg-CCN2 21.3 ± 0.4 μg/mg dry weight, p<0.01). Interestingly, this difference was reversed at 42 days post-MI, where infarct region collagen contents were lower in Tg-CCN2 mice versus NTC mice (114.3 ± 6.1 vs 88.9 ± 8.6 μg/mg dry weight, p < 0.05). The enhanced deposition in Tg-CCN2 mice reflected in a lower incidence of myocardial rupture in Tg-CCN2 vs NTC mice (2/41 vs 10/39, p = 0.01). Interestingly, rCCN2 reduced TGFβ-induced differentiation of fibroblasts reflected by reduced upregulation of α-smooth muscle actin. Impaired myofibroblast phenotype following exposure to rCCN2 also manifested in both reduced myofibroblast migration by 27±4% (p<0.05, n=4) and proliferation by 70±5% (p< 0.05, n=6). The mechanism of the reduced sensitivity of cardiac fibroblasts to TGFβ-induced myofibroblast transformation after prolonged exposure to rCCN2 (48h) was reduced TGFβ-stimulated phosphorylation of Smad2[Ser465/467] (59±2% reduction, p<0.001, n=3). In conclusion, we show that infarct healing is enhanced in Tg-CCN2 mice. Yet, CCN2 limits collagen deposition and myocardial fibrosis in ischemic heart failure by reducing the sensitivity of cardiac fibroblasts to TGFβ.
- © 2013 by American Heart Association, Inc.