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

• Published in: Protein & cell Vol. 13; no. 5; pp. 336 - 359
• Main Authors: Jiang, Kai, Xu, Yue, Wang, Dandan, Chen, Feng, Tu, Zizhuo, Qian, Jie, Xu, Sheng, Xu, Yixiang, Hwa, John, Li, Jian, Shang, Hongcai, Xiang, Yaozu
• Format: Journal Article
• Language: English
• Published: Beijing Higher Education Press 01.05.2022; Springer Nature B.V
• Subjects: Animal models; Animals; Autophagy; autosis; Biochemistry; Biomedical and Life Sciences; Cardiomyocytes; cardioprotection; Cardiovascular diseases; Cell Biology; Cell death; Congestive heart failure; Developmental Biology; Diabetes; Diabetes Mellitus; Diabetes Mellitus, Type 2 - drug therapy; Drug development; empagliflozin; Fibrosis; Glucose; Heart attacks; Human Genetics; Humans; Ischemia; Life Sciences; Mice; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Na+/H+-exchanging ATPase; NHE1; Patients; Protein Science; Research Article; SGLT2 inhibitors; Sodium-glucose cotransporter; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Starvation; Stem Cells; Ventricle; Ventricular Remodeling; empagliflozin; cardioprotection; NHE1; autosis; myocardial infarction; SGLT2 inhibitors
• ISSN: 1674-800X; 1674-8018; 1674-8018
• DOI: 10.1007/s13238-020-00809-4

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.