P402Targeted deletion of the p66ShcA adaptor protein attenuates adverse cardiac remodeling after myocardial infarction by modulation of extracellular matrix

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Cardiac fibrosis is a crucial factor for the development of heart failure (HF) due to coronary artery disease (CAD). The ShcA gene encodes for three isoforms, p42-, p46- and p66ShcA, and is indispensible for cardiac extracellular matrix integrity. Targeted deletion of p66ShcA facilitates fibroblast function and cutaneous wound healing, and is cardioprotective during ischemia/reperfusion injury. We hypothesized that (1) p66ShcA is expressed during CAD in humans, and (2) p66ShcA aggravates cardiac fibrosis postinfarction in mice. Materials p66ShcA expression was evaluated in left ventricular tissue from patients with either CAD undergoing coronary artery bypass surgery (NYHA II-III, left ventricular (LV) ejection fraction (EF) > 60 %) (n=8) or from patients with end-stage HF undergoing transplantation due to CAD (n=8) and dilated cardiomyopathy (n=16) (NYHA III-IV, LVEF < 35 %). Myocardium of healthy donors with non-cardiac death served as controls (n=7). To evaluate a role of p66Shc in postinfarction remodeling, p66ShcA knockout mice (p66KO) were subjected to permanent in vivo occlusion of the left coronary artery and compared with wild type littermates. Cardiac fibrosis was assessed by picrosirius red staining (n=5 per group) 6 weeks postinfarction. In addition, hearts from wild type and p66KO (n=5 per group) were harvested three days postinfarction for evaluation of mRNA expression of connective tissue growth factor (CTGF), thrombospondin1 (real time PCR) and matrix metalloproteinase 2 (MMP-2) (gel zymography).


Expression of mRNA for p66ShcA was increased in myocardium of patients with CAD-associated with mild dysfunction (p=0,03) but not with end-stage HF due to CAD (p=0,8) or dilated cardiomyopathy (p=0,3). Previously we reported that p66KO are protected against heart rupture and LV dilatation. The present study shows that p66ShcA deletion attenuated fibrosis in the septal wall of LV remote from the infarct (p=0,02). The observed phenomenon was associated with alternation of extracellular matrix protein expression. MMP-2 (p=0,008), CTGF (p=0,02) and thrombospondin-1(p=0,02) were downregulated in infarcted hearts of p66KO mice as compared to wild type on the third day postinfarction.


The p66ShcA is increased in the hearts of patients with CAD and preserved function, but not in the myocardium of CAD patients with HF. p66KO had altered expression of the matrix proteins after myocardial infarction. The p66ShcA adaptor protein may deteriorate myocardial healing and contribute to cardiac fibrosis. Thus, p66ShcA might potentially be a new target for anti-fibrotic therapy.

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