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
Affiliations
Chen Cai
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
Zhongzhou Guo
Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
Xing Chang
Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
Ziying Li
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
Feng Wu
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
Jing He
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
Tiantian Cao
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
Kangrong Wang
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
Nengxian Shi
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
Hao Zhou
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WYWY, 82071, USA
Sam Toan
Department of Chemical Engineering, University of Minnesota-Duluth, Duluth, MN, 55812, USA
David Muid
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Ying Tan
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China; Corresponding author.
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.
