Sodium-glucose cotransporter 2(SGLT2)inhibitors reduce cardiovascular mortality in patients with dia-betes mellitus but the protective mechanism remains elusive.Here we demonstrated that the SGLT2 inhibitor,Empagliflozin(EMPA),suppresses cardiomyocytes autosis(autophagic cell death)to confer cardioprotec-tive effects.Using myocardial infarction(Ml)mouse models with and without diabetes mellitus,EMPA treat-ment 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 regu-late excessive autophagy.Knockdown of NHE1 signifi-cantly rescued glucose deprivation-induced autosis.In contrast,overexpression of NHE1 aggravated the car-diomyocytes 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.

Kai Jiang;Yue Xu;Dandan Wang;Feng Chen;Zizhuo Tu;Jie Qian;Sheng Xu;Yixiang Xu;John Hwa;Jian Li;Hongcai Shang;Yaozu Xiang

Shanghai East Hospital,School of Life Sciences and Technology,Tongji University,Shanghai 200092,China;State Key Laboratory of Bioreactor Engineering,Shanghai Key Laboratory of New Drug Design,East China University of Science and Technology,Shanghai 200237,China;Section of Cardiovascular Medicine,Department of Internal Medicine,Yale Cardiovascular Research Center,Yale University School of Medicine,New Haven,CT 06511,USA;Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine,Beijing 100700,China

蛋白质与细胞

[1]Kai Jiang;Yue Xu;Dandan Wang;Feng Chen;Zizhuo Tu;Jie Qian;Sheng Xu;Yixiang Xu;John Hwa;Jian Li;Hongcai Shang;Yaozu Xiang-.Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis)[J].蛋白质与细胞,2022(05):336-359

Cardioprotective,autosis,Empagliflozin,cardioprotec,diomyocytes

mechanism,SGLT2,against,myocardial,infarction,through,reduction,Sodium,glucose,cotransporter,inhibitors,cardiovascular,mortality,patients,mellitus,but,remains,elusive,Here,we,demonstrated,that,EMPA,suppresses,cardiomyocytes,autophagic,cell,death,confer,effects,Using,Ml,mouse,models,without,diabetes,significantly,reduced,size,fibrosis,thereby,leading,improved,cardiac,function,survival,In,context,ischemia,nutritional,deprivation,where,already,highly,stimulated,directly,inhibits,activity,Na+,H+exchanger,NHE1,excessive,autophagy,Knockdown,rescued,induced,contrast,overexpression,aggravated,response,starvation,which,was,effectively,treatment,Furthermore,vitro,vivo,analysis,Beclin,knockout,mice,validated,cardioprotective,are,least,part,downregulation,flux,These,findings,provide,new,insights,drug,development,specifically,targeting,ventricular,remodeling,heart,failure,after,both,diabetic

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