Abstract 14972: Sestrin2 Prevents Excessive Cardiac Ischemia/Reperfusion Injury by Regulating Unfolded Protein Response

Abstract

Introduction: Cardiac ischemia/reperfusion (I/R) can alter redox and calcium homeostasis, causing proteins misfolded or unfolded in endoplasmic reticulum (ER) and activating unfolded protein response (UPR). Appropriate UPR is an adaptive response of the cell, however excessive and prolonged UPR can further deteriorate calcium overload and reactive oxygen species (ROS) overproduction. We have found that Sestrin2 (Sesn2), an endogenous inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) is upregulated after cardiac I/R and lack of Sesn2 in hearts may cause more severe I/R injury. Hypothesis: Sesn2 maintains the ER homeostasis as an adaptive response to attenuate calcium overload and reduce ROS overproduction during myocardial I/R. Methods: Ligation/release of the left anterior descending coronary arteries (LAD) were performed in the C57BL/6J and cardiac specific Sesn2 knock out (Sens2 cKO ) mice to induce myocardial I/R injury. Results: We found that absence of Sesn2 in the hearts increased myocardial infarction by 49.4%, and decreased the systolic function of the heart by 22.9%, compared to wild type (WT) mice. I/R-induced UPR is a time-dependent process, and it reached its peak at 6 hours post reperfusion, but returned to normal after 24 hours of reperfusion in WT mice, however, Sesn2 deficiency resulted in higher and prolonged activation curve of UPR, as well as more myocardial apoptosis, compared to WT mice. We also found that Sesn2 deficiency impaired calcium transient and increased ROS after I/R. Furthermore, the activation of mTORC1 pathway after I/R was also significantly increased and prolonged in Sesn2 cKO hearts. Inhibiting the mTORC1 by rapamycin after I/R reduced myocardial apoptosis in both WT and Sesn2 cKO mice. Conclusions: During I/R, the regulation of the mTORC1 signaling pathway by Sesn2 may be a key factor in maintaining ER homeostasis to reduce cardiac I/R injury.