Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis
| Autor: | Hongcai Shang, Dandan Wang, Yaozu Xiang, John Hwa, Sheng Xu, Feng Chen, Zizhuo Tu, Yixiang Xu, Jie Qian, Yue Xu, Jian Li, Kai Jiang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Myocardial Infarction 030204 cardiovascular system & hematology Pharmacology Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Drug Discovery Diabetes Mellitus medicine Animals Humans Ventricular remodeling Sodium-Glucose Transporter 2 Inhibitors Cardioprotection Ventricular Remodeling business.industry Autophagy Cell Biology medicine.disease Glucose 030104 developmental biology Diabetes Mellitus Type 2 chemistry Knockout mouse Myocardial fibrosis SGLT2 Inhibitor business Biotechnology EMPA |
| Zdroj: | Protein & Cell. 13:336-359 |
| ISSN: | 1674-8018 |
| DOI: | 10.1007/s13238-020-00809-4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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