Abstract 16488: Sestrin2 Protects Against Long-Term Cardiac Injury and Remodeling by Modulating mTORC1 Activation in Myocardial Ischemia/Reperfusion

Abstract

Introduction: Myocardial ischemia/reperfusion (I/R) injury can lead to long-term cardiac dysfunction and heart failure with reduced ejection fraction (HFrEF) in aged hearts. However, young hearts may exhibit some resistance to this process and retain better cardiac function. Our previous studies have identified a novel protein called Sestrin2 (Sesn2), which is downregulated in aged hearts. Hypothesis: Sesn2 may protect hearts from progressing to HFrEF following myocardial I/R. Methods: We induced myocardial I/R injury by ligation/release of the left anterior descending coronary arteries (LAD) in both C57BL/6J mice and mice with cardiac-specific Sesn2 knockout (Sesn2 cKO ). Cardiac function was assessed, and samples were collected at baseline, one day post I/R, seven days post I/R, and 28 days post I/R. Results: In wild-type (WT) hearts (12-18 weeks), cardiac function showed a slight decrease 28 days post I/R (IR28D), but the ejection fraction (EF) remained above 50%. However, Sesn2 cKO mice exhibited a significant reduction in cardiac function at IR28D, with an about 27.5% decrease in EF compared to WT hearts. We also observed a significant increase in volume at diastole in Sesn2 cKO mice at IR28D compared to their baseline and corresponding WT. Furthermore, when comparing mitochondrial respiration in the area at risk (AAR) of the left ventricles between the two groups, we found a significant decrease in oxygen consumption rate (OCR) and a significant increase in H 2 O 2 production in Sesn2 cKO hearts. Additionally, the mammalian target of rapamycin complex 1 (mTORC1) was significantly upregulated in Sesn2 cKO mice compared to WT hearts. Conclusions: Sesn2 exerts a cardiac protective effect by downregulating mTORC1 activation, thereby reducing long-term cardiac injury following I/R, attenuating cardiac remodeling, and improving mitochondrial respiration in the AAR of the heart.