Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis

• DOI: 10.1186/s12933-022-01532-6
• Publication Date: 2022-06-15T16:04:32Z
• Authors: Rongjun Zou; Wanting Shi; Junxiong Qiu; Na Zhou; Na Du; Hao Zhou; Xinxin Chen; Li Ma
• Keywords: Dynamins; 0301 basic medicine; Microvascular injury; Empagliflozin; Apoptosis; Myocardial Reperfusion Injury; ischemia/reperfusion injury; Mitochondrial Dynamics; Mitochondrial Proteins; Mice; 03 medical and health sciences; Glucosides; Ischemia; Diseases of the circulatory (Cardiovascular) system; Animals; Homeostasis; Endothelial dysfunction; Benzhydryl Compounds; Research; Endothelial Cells; DNA; Mitochondria; 3. Good health; RC666-701; Reperfusion Injury

AbstractBackgroundEmpagliflozin has been reported to protect endothelial cell function, regardless of diabetes status. However, the role of empagliflozin in microvascular protection during myocardial ischemia reperfusion injury (I/R) has not been fully understood.MethodsElectron microscopy, western blots, immunofluorescence, qPCR, mutant plasmid transfection, co-immunoprecipitation were employed to explore whether empagliflozin could alleviate microvascular damage and endothelial injury during cardiac I/R injury.ResultsIn mice, empagliflozin attenuated I/R injury-induced microvascular occlusion and microthrombus formation. In human coronary artery endothelial cells, I/R injury led to adhesive factor upregulation, endothelial nitric oxide synthase inactivation, focal adhesion kinase downregulation, barrier dysfunction, cytoskeletal degradation and cellular apoptosis; however, empagliflozin treatment diminished these effects. Empagliflozin improved mitochondrial oxidative stress, mitochondrial respiration and adenosine triphosphate metabolism in I/R-treated human coronary artery endothelial cells by preventing the phosphorylation of dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1), thus repressing mitochondrial fission. The protective effects of empagliflozin on mitochondrial homeostasis and endothelial function were abrogated by the re-introduction of phosphorylated Fis1, but not phosphorylated Drp1, suggesting that Fis1 dephosphorylation is the predominant mechanism whereby empagliflozin inhibits mitochondrial fission during I/R injury. Besides, I/R injury induced Fis1 phosphorylation primarily by activating the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) pathway, while empagliflozin inactivated this pathway by exerting anti-oxidative effects.ConclusionsThese results demonstrated that empagliflozin can protect the microvasculature by inhibiting the DNA-PKcs/Fis1/mitochondrial fission pathway during myocardial I/R injury.