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

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...

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Autores principales: Jiang, Kai, Xu, Yue, Wang, Dandan, Chen, Feng, Tu, Zizhuo, Qian, Jie, Xu, Sheng, Xu, Yixiang, Hwa, John, Li, Jian, Shang, Hongcai, Xiang, Yaozu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Higher Education Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008115/
https://www.ncbi.nlm.nih.gov/pubmed/33417139
http://dx.doi.org/10.1007/s13238-020-00809-4
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author Jiang, Kai
Xu, Yue
Wang, Dandan
Chen, Feng
Tu, Zizhuo
Qian, Jie
Xu, Sheng
Xu, Yixiang
Hwa, John
Li, Jian
Shang, Hongcai
Xiang, Yaozu
author_facet Jiang, Kai
Xu, Yue
Wang, Dandan
Chen, Feng
Tu, Zizhuo
Qian, Jie
Xu, Sheng
Xu, Yixiang
Hwa, John
Li, Jian
Shang, Hongcai
Xiang, Yaozu
author_sort Jiang, Kai
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13238-020-00809-4) contains supplementary material, which is available to authorized users
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spelling pubmed-90081152022-04-27 Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis Jiang, Kai Xu, Yue Wang, Dandan Chen, Feng Tu, Zizhuo Qian, Jie Xu, Sheng Xu, Yixiang Hwa, John Li, Jian Shang, Hongcai Xiang, Yaozu Protein Cell Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13238-020-00809-4) contains supplementary material, which is available to authorized users Higher Education Press 2021-01-08 2022-05 /pmc/articles/PMC9008115/ /pubmed/33417139 http://dx.doi.org/10.1007/s13238-020-00809-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Jiang, Kai
Xu, Yue
Wang, Dandan
Chen, Feng
Tu, Zizhuo
Qian, Jie
Xu, Sheng
Xu, Yixiang
Hwa, John
Li, Jian
Shang, Hongcai
Xiang, Yaozu
Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis
title Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis
title_full Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis
title_fullStr Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis
title_full_unstemmed Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis
title_short Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis
title_sort cardioprotective mechanism of sglt2 inhibitor against myocardial infarction is through reduction of autosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008115/
https://www.ncbi.nlm.nih.gov/pubmed/33417139
http://dx.doi.org/10.1007/s13238-020-00809-4
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