恩帕吉菲
自噬
糖尿病
医学
下调和上调
心肌梗塞
药理学
基因剔除小鼠
心脏病学
内科学
化学
细胞凋亡
糖尿病性心肌病
内分泌学
心力衰竭
2型糖尿病
心肌病
生物化学
受体
基因
作者
Kai Jiang,Yue Xu,Dandan Wang,Feng Chen,Zizhuo Tu,Jie Qian,Sheng Xu,Yixiang Xu,John Hwa,Jian Li,Hongcai Shang,Yaozu Xiang
出处
期刊:Protein & Cell
[Springer Nature]
日期:2021-01-08
卷期号:13 (5): 336-359
被引量:59
标识
DOI:10.1007/s13238-020-00809-4
摘要
Abstract 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.
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