Apr 28, 2020

Clearance of senescent cells during cardiac ischemia-reperfusion injury improves heart recovery following myocardial infarction

BioRxiv : the Preprint Server for Biology
E. DookunGavin D Richardson

Abstract

Rationale: A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. We have previously shown that oxidative stress induces myocardial senescence, promoting adverse myocardial remodeling and cardiac dysfunction via the expression of a proinflammatory senescence-associated secretory phenotype (SASP). In this study we hypothesized that oxidative stress-induced senescence and SASP-mediated inflammation contribute to the pathophysiology of cardiac IRI and thus, senescence represents a novel therapeutic target. Objective: To identify if cellular senescence contributes to the pathophysiology of IRI and to investigate if pharmacological elimination of senescent cells after ischemia-reperfusion can improve cardiac outcomes. Methods and Results: Using an established model of cardiac ischemia-reperfusion, we demonstrate that in young mice IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations. Additionally, we show that treatment with the senolytic drug navitoclax improves left ventricular function, increases myocardial vasculariz...Continue Reading

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