title: The p66ShcA adaptor protein regulates healing after myocardial infarction.
abstract: 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.
authors: Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, Postbox 1103, Blindern, 0317, Oslo, Norway, anton.baysa.md@gmail.com.
authors: Anton
authors: A
authors: Baysa
authors: Julia
authors: J
authors: Sagave
authors: Andrea
authors: A
authors: Carpi
authors: Tania
authors: T
authors: Zaglia
authors: Marika
authors: M
authors: Campesan
authors: Christen P
authors: CP
authors: Dahl
authors: Dusan
authors: D
authors: Bilbija
authors: Maria
authors: M
authors: Troitskaya
authors: Lars
authors: L
authors: Gullestad
authors: Marco
authors: M
authors: Giorgio
authors: Marco
authors: M
authors: Mongillo
authors: Fabio
authors: F
authors: Di Lisa
authors: Jarle I
authors: JI
authors: Vaage
authors: Guro
authors: G
authors: Valen
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020778:Matrix Metalloproteinase 2