The p66ShcA adaptor protein regulates healing after myocardial infarction

• Published in: Basic research in cardiology 2015-03, Vol.110 (2), p.13-13, Article 13
• Main Authors: Baysa, Anton, Sagave, Julia, Carpi, Andrea, Zaglia, Tania, Campesan, Marika, Dahl, Christen P., Bilbija, Dusan, Troitskaya, Maria, Gullestad, Lars, Giorgio, Marco, Mongillo, Marco, Di Lisa, Fabio, Vaage, Jarle I., Valen, Guro
• Format: Article
• Language: English
• Subjects: Aged; Animals; Blotting, Western; Cardiology; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 2 - biosynthesis; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Original Contribution; Oxidative Stress - physiology; Real-Time Polymerase Chain Reaction; Shc Signaling Adaptor Proteins - metabolism; Src Homology 2 Domain-Containing, Transforming Protein 1; Ventricular Remodeling - physiology
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-015-0470-0

Heart rupture and heart failure are deleterious complications of myocardial infarction. The ShcA gene encodes for three protein isoforms, p46-, p52- and p66ShcA. p66ShcA induces oxidative stress. We studied the role of p66ShcA post-infarction. Expression of p66ShcA was analyzed in myocardium of patients with stable angina ( n  = 11), in explanted hearts with end-stage ischemic heart failure ( n  = 9) and compared to non-failing hearts not suitable for donation ( n  = 7). p66ShcA was increased in the patients with stable angina, but not in the patients with end-stage heart failure. Mice ( n  = 105) were subjected to coronary artery ligation. p66ShcA expression and phosphorylation were evaluated over a 6-week period. p66ShcA expression increased transiently during the first weeks post-infarction. p66ShcA knockout mice (KO) were compared to wild type ( n  = 82 in total). KO had improved survival and reduced occurrence of heart rupture post-infarction. Expression of cardiac matrix metalloproteinase 2 (MMP-2) was reduced; fibroblast activation and collagen accumulation were facilitated, while oxidative stress was attenuated in KO early post-infarction. 6 weeks post-infarction, reactive fibrosis and left ventricular dilatation were diminished in KO. p66ShcA regulation of MMP-2 was demonstrated in cultured fibroblasts: lack or overexpression of p66ShcA in vitro altered expression of MMP-2. Myocardial infarction induced cardiac p66ShcA. Deletion of p66ShcA improved early survival, myocardial healing and reduced cardiac fibrosis. Upon myocardial infarction p66ShcA regulates MMP-2 activation. The role of p66ShcA in human cardiac disease deserves further study as a potential target for reducing adverse cardiac remodeling post-infarction.