Abstract 20107: The Matricellular Protein CCN2/CTGF Attenuates Ventricular Remodeling by Enhancing Scar Healing after Myocardial Infarction
We have previously shown that left ventricular (LV) remodeling after myocardial infarction (MI) is attenuated in transgenic mice with cardiac-restricted overexpression of CCN2 (Tg-CCN2) regardless of reperfusion of the ischemic area or not. Thus, the aim of this study was to resolve to what extent the role of CCN2 in scar healing may mechanistically contribute to attenuation of LV dilatation after MI.
MI was induced by ligation of the left coronary artery in Tg-CCN2 and in non-transgenic control (NTC) mice. Area of necrosis and LV dimensions were determined by cardiac MRI. Primary cultures of cardiac fibroblasts (cFBs) were prepared from NTC mice and stimulated with or without recombinant CCN2 (rCCN2; 200 nmol/L).
Area of necrosis 24 hours after induction of MI was similar in Tg-CCN2 and NTC mice. Serial cardiac MRI examinations at day 1, 7, 14, and 42 after induction of MI revealed that CCN2 engendered robust inhibition of LV dilatation during the first week after MI, i.e. the period of infarct dilatation (LV end-diastolic volume at day 7: 97±9 vs. 136±7 μL in Tg-CCN2 vs. NTC mice; p<0.01). Concurrently, we found enhanced deposition of collagen in the developing scar tissue of Tg-CCN2 mice from day 5 after MI (21.3±0.4 vs. 16.6±0.8 μg/mg dry weight in Tg-CCN2 vs. NTC; p<0.01). This decreased LV dilatation and accelerated collagen deposition also reflected in reduced incidence of infarct rupture in Tg-CCN2 vs. NTC mice (2/41 vs. 10/39, p<0.05) during the first week after MI. Stimulation of cFBs with rCCN2 in vitro evoked robust increase of collagen synthesis (+66±3%, p<0.05, n=6) corroborating the in vivo finding of Tg-CCN2 mice. Gene set enrichment analysis of rCCN2-stimulated cFBs also revealed increased expression of NFkB target genes and induction of an inflammatory phenotype (false discovery rate <0.05) that was capable of mediating caspase-1-dependent, paracrine senescence of cFBs.
In conclusion, this study demonstrates that CCN2 enhances healing of MI and that the accelerated scar tissue formation during the first week after MI contributes to reduced LV dilatation and reduced incidence of infarct rupture. CCN2 stimulates an inflammatory cFB phenotype that promotes senescence of cFBs, providing a plausible mechanism for the enhanced, yet limited scar formation.
Author Disclosures: O.J. Kaasboell: None. G. Florholmen: None. M. Aronsen: None. E. Gao: None. I.T. Moe: None. W.J. Koch: None. I. Sjaastad: None. S.M. Ahmed: None. H. Attramadal: None.
- © 2014 by American Heart Association, Inc.