Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

Chen Cai, Zhongzhou Guo, Xing Chang, Ziying Li, Feng Wu, Jing He, Tiantian Cao, Kangrong Wang, Nengxian Shi, Hao Zhou, Sam Toan, David Muid, Ying Tan

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Mitophagy preserves microvascular structure and function during myocardial ischemia/reperfusion (I/R) injury. Empagliflozin, an anti-diabetes drug, may also protect mitochondria. We explored whether empagliflozin could reduce cardiac microvascular I/R injury by enhancing mitophagy. In mice, I/R injury induced luminal stenosis, microvessel wall damage, erythrocyte accumulation and perfusion defects in the myocardial microcirculation. Additionally, I/R triggered endothelial hyperpermeability and myocardial neutrophil infiltration, which upregulated adhesive factors and endothelin-1 but downregulated vascular endothelial cadherin and endothelial nitric oxide synthase in heart tissue. In vitro, I/R impaired the endothelial barrier function and integrity of cardiac microvascular endothelial cells (CMECs), while empagliflozin preserved CMEC homeostasis and thus maintained cardiac microvascular structure and function. I/R activated mitochondrial fission, oxidative stress and apoptotic signaling in CMECs, whereas empagliflozin normalized mitochondrial fission and fusion, neutralized supraphysiologic reactive oxygen species concentrations and suppressed mitochondrial apoptosis. Empagliflozin exerted these protective effects by activating FUNDC1-dependent mitophagy through the AMPKα1/ULK1 pathway. Both in vitro and in vivo, genetic ablation of AMPKα1 or FUNDC1 abolished the beneficial effects of empagliflozin on the myocardial microvasculature and CMECs. Taken together, the preservation of mitochondrial function through an activation of the AMPKα1/ULK1/FUNDC1/mitophagy pathway is the working mechanism of empagliflozin in attenuating cardiac microvascular I/R injury.

Original languageEnglish (US)
Article number102288
JournalRedox Biology
Volume52
DOIs
StatePublished - Jun 2022

Bibliographical note

Funding Information:
This study is supported by the National Natural Science Foundation of China (NO. 82102262 , NO. 82170241 , NO. 81900252 ) and Guangdong Basic and Applied Basic Research Foundation (NO. 2021A1515010977 and NO. 2020A1515110174 ).

Publisher Copyright:
© 2022 The Authors

Keywords

  • AMPKα1/ULK1 pathway
  • Cardiac microvascular I/R injury
  • Empagliflozin
  • FUNDC1-Dependent mitophagy

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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