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Published on: September 15, 2023
The p66ShcA adaptor protein regulates healing after myocardial infarction
Anton Baysa1, Julia Sagave, Andrea Carpi
1Division 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.
Insights
p66ShcA protein exacerbates heart damage after myocardial infarction by increasing oxidative stress and cardiac fibrosis. Eliminating p66ShcA improved survival and reduced heart rupture in mice, suggesting it as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Stress Response
Background:
- Myocardial infarction (MI) can lead to heart rupture and failure.
- The ShcA gene encodes protein isoforms, including p66ShcA, which is implicated in oxidative stress.
- The role of p66ShcA in post-MI cardiac remodeling is not fully understood.
Purpose of the Study:
- To investigate the role of p66ShcA in the cardiac response to myocardial infarction.
- To determine the impact of p66ShcA deletion on post-MI survival, cardiac rupture, and remodeling.
- To explore the molecular mechanisms by which p66ShcA influences cardiac healing.
Main Methods:
- Analysis of p66ShcA expression in human myocardial tissue from patients with stable angina and heart failure.
- Induction of myocardial infarction in mice, followed by evaluation of p66ShcA expression and phosphorylation over 6 weeks.
- Comparison of survival, cardiac rupture, fibrosis, and ventricular remodeling between p66ShcA knockout mice and wild-type littermates.
- In vitro studies using cultured fibroblasts to assess the regulation of matrix metalloproteinase-2 (MMP-2) by p66ShcA.
Main Results:
- p66ShcA expression was elevated in stable angina patients but not in end-stage heart failure.
- p66ShcA expression increased transiently in mice post-MI.
- p66ShcA knockout mice exhibited improved survival, reduced heart rupture, attenuated oxidative stress, and diminished cardiac fibrosis and left ventricular dilatation.
- p66ShcA deletion led to reduced MMP-2 expression and altered fibroblast activation and collagen accumulation.
- p66ShcA was shown to regulate MMP-2 expression in cultured fibroblasts.
Conclusions:
- Myocardial infarction induces cardiac p66ShcA expression.
- Deletion of p66ShcA significantly improves survival, myocardial healing, and reduces cardiac fibrosis post-MI.
- p66ShcA plays a critical role in regulating MMP-2 activation and adverse cardiac remodeling following myocardial infarction.
- p66ShcA represents a potential therapeutic target for mitigating adverse cardiac remodeling after MI.
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.
