Senescence as a potential therapeutic target for ischaemia-reperfusion injury following acute myocardial infarction

Abstract

Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide. The gold-standard intervention is reperfusion via primary percutaneous coronary intervention, however, reperfusion can induce ischaemia-reperfusion injury (IRI). A key component of IRI is increased oxidative stress and MI patients often exhibit progressive remodelling resulting in heart failure. This lab has previously demonstrated that during ageing, oxidative stress drives senescence which contributes to myocardial remodeling via the senescence-associated secretory phenotype (SASP), including pro-hypertrophic and pro-fibrotic proteins. I therefore hypothesised following MI with IRI cellular stress induces senescence which contributes to adverse remodeling via similar mechanisms. Three-month-old mice underwent 60-minute ligation of the left anterior descending coronary artery (LAD) followed by reperfusion, and were assessed for characteristics of senescence. To test the impact of senescence post-MI with IRI, I eliminated senescent cells pharmacologically using the senolytic drug navitoclax, or targeted deletion of p16Ink4a in cardiomyocytes using a novel mouse model (p16-MerCreMer). Hearts were assessed using histological and qRT-PCR analysis. Cardiac function was assessed via magnetic resonance imaging. As expected, LAD ligation resulted in a typical intramural infarct and reduction in cardiac function. A significant increase in senescence markers was observed in both cardiomyocytes and interstitial cells. Mice treated with Navitoclax demonstrated a significant reduction in senescence markers as well as a global reduction in SASP and remodelling gene expression. Functionally, treated mice improved at 5 weeks post-LAD compared to controls, which may be explained by their reduced scar size. In comparison, the p16-MerCreMer mouse was insufficient to attenuate remodelling and demonstrated no functional improvement. Analysis by cytokine array demonstrated a decline in several SASP factors during navitoclax treatment and in vitro studies suggest a fibrotic SASP may detrimentally impact cardiomyocytes and angiogenesis. These data suggest that eliminating senescent cells or attenuating the SASP are viable strategies to improve outcome following IRI.