文献类型：期刊文献

英文题名：Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis

作者：Jiang, Kai[1];Xu, Yue[1];Wang, Dandan[1];Chen, Feng[1];Tu, Zizhuo[1];Qian, Jie[1];Xu, Sheng[1];Xu, Yixiang[2];Hwa, John[3];Li, Jian[2];Shang, Hongcai[4];Xiang, Yaozu[1]

机构：[1]Tongji Univ, Sch Life Sci & Technol, Shanghai East Hosp, Shanghai 200092, Peoples R China;[2]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Yale Univ, Sch Med, Sect Cardiovasc Med, Dept Internal Med,Yale Cardiovasc Res Ctr, New Haven, CT 06511 USA;[4]Beijing Univ Chinese Med, Key Lab Chinese Internal Med, Minist Educ & Beijing, Dongzhimen Hosp, Beijing 100700, Peoples R China

年份：2022

卷号：13

期号：5

起止页码：336

外文期刊名：PROTEIN & CELL

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000606252600001)】；

基金：Y Xiang received support from the National Key Research and Development Program of China (2017YFC1700402), National Outstanding Youth Science Fund Project of National Natural Science Foundation of China (81822048 and 81770256) and Fund of Shanghai Pudong New Area (PDZY-2018-0603).

语种：英文

外文关键词：myocardial infarction; SGLT2 inhibitors; empagliflozin; cardioprotection; NHE1; autosis

摘要：Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive. Here we demonstrated that the SGLT2 inhibitor, Empagliflozin (EMPA), suppresses cardiomyocytes autosis (autophagic cell death) to confer cardioprotective effects. Using myocardial infarction (MI) mouse models with and without diabetes mellitus, EMPA treatment significantly reduced infarct size, and myocardial fibrosis, thereby leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, EMPA directly inhibits the activity of the Na+/H+ exchanger 1 (NHE1) in the cardiomyocytes to regulate excessive autophagy. Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis. In contrast, overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation, which was effectively rescued by EMPA treatment. Furthermore, in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA's cardioprotective effects are at least in part through downregulation of autophagic flux. These findings provide new insights for drug development, specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after MI in both diabetic and non-diabetic patients.