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Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis

查看全文 作　　者：Kai [1]Jiang;Yue [1]Xu;Dandan [1]Wang;Feng [1]Chen;Zizhuo [1]Tu;Jie [1]Qian;Sheng [1]Xu;Yixiang [2]Xu;John [3]Hwa;Jian [2]Li;Hongcai [4]Shang;Yaozu [1]Xiang 高影响力作者 机构地区：[1]Shanghai East Hospital,School of Life Sciences and Technology,Tongji University,Shanghai 200092,China;[2]State Key Laboratory of Bioreactor Engineering,Shanghai Key Laboratory of New Drug Design,East China University of Science and Technology,Shanghai 200237,China;[3]Section of Cardiovascular Medicine,Department of Internal Medicine,Yale Cardiovascular Research Center,Yale University School of Medicine,New Haven,CT 06511,USA;[4]Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine,Beijing 100700,China高影响力机构 出　　处：《Protein & Cell》索引2022年第13卷第5期,共24页高影响力期刊 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);Fund of Shanghai Pudong New Area(PDZY-2018-0603). 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(Ml)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 Ml in both diabetic and non-diabetic patients. 关 键 词：myocardial infarction SGLT2 inhibitors empagliflozin CARDIOPROTECTION NHE1 autosis
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