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. In this study, we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS-based proteomics revealed that biological processes associated with fibrosis and inflammation that were increased following ischemia-reperfusion were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of pro-inflammatory, profibrotic, and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16, and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time-point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.

Biosciences Institute Newcastle University Newcastle upon Tyne UK

Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA

Faculty of Pharmacy Charles University Prague Czech Republic

INSERM I2MC University of Toulouse Toulouse France

School of Environmental Sciences Faculty of Science Agriculture and Engineering Newcastle University Newcastle upon Tyne UK

School of Medicine Dentistry and Biomedical Sciences Centre for Experimental Medicine Institute for Health Sciences Queen`s University Belfast Belfast UK

Translational and Clinical Research Newcastle University Newcastle upon Tyne UK

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