Dataset Information

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

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.

SUBMITTER: Jiang K

PROVIDER: S-EPMC9008115 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Jiang Kai K Xu Yue Y Wang Dandan D Chen Feng F Tu Zizhuo Z Qian Jie J Xu Sheng S Xu Yixiang Y Hwa John J Li Jian J Shang Hongcai H Xiang Yaozu Y

Protein & cell 20210108 5

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 ...[more]

PMID: 33417139

Similar Datasets

Project description:BackgroundSodium-glucose co-transporter 2 inhibitors (SGLT2-i) have shown significant cardiovascular benefits in patients with and without type 2 diabetes mellitus (T2DM). They have also gained interest for their potential anti-arrhythmic role and their ability to reduce the occurrence of atrial fibrillation (AF) and ventricular arrhythmias (VAs) in T2DM and heart failure patients.ObjectivesTo investigate in-hospital new-onset cardiac arrhythmias in a cohort of T2DM patients presenting with acute myocardial infarction (AMI) treated with SGLT2-i vs. other oral anti-diabetic agents (non-SGLT2-i users).MethodsPatients from the SGLT2-I AMI PROTECT registry (NCT05261867) were stratified according to the use of SGLT2-i before admission for AMI, divided into SGLT2-i users vs. non-SGLT2-i users. In-hospital outcomes included the occurrence of in-hospital new-onset cardiac arrhythmias (NOCAs), defined as a composite of new-onset AF and sustained new-onset ventricular tachycardia (VT) and/or ventricular fibrillation (VF) during hospitalization.ResultsThe study population comprised 646 AMI patients categorized into SGLT2-i users (111 patients) and non-SGLT2-i users (535 patients). SGLT2-i users had a lower rate of NOCAs compared with non-SGLT2-i users (6.3 vs. 15.7%, p = 0.010). Moreover, SGLT2-i was associated with a lower rate of AF and VT/VF considered individually (p = 0.032). In the multivariate logistic regression model, after adjusting for all confounding factors, the use of SGLT2-i was identified as an independent predictor of the lower occurrence of NOCAs (OR = 0.35; 95%CI 0.14-0.86; p = 0.022). At multinomial logistic regression, after adjusting for potential confounders, SGLT2-i therapy remained an independent predictor of VT/VF occurrence (OR = 0.20; 95%CI 0.04-0.97; p = 0.046) but not of AF occurrence.ConclusionsIn T2DM patients, the use of SGLT2-i was associated with a lower risk of new-onset arrhythmic events during hospitalization for AMI. In particular, the primary effect was expressed in the reduction of VAs. These findings emphasize the cardioprotective effects of SGLT2-i in the setting of AMI beyond glycemic control.Trial registrationData are part of the observational international registry: SGLT2-I AMI PROTECT. ClinicalTrials.gov, identifier: NCT05261867.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets