SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways

Background: Given the importance of microvascular injury in infarct formation and expansion, development of therapeutic strategies for microvascular protection against myocardial ischemia/reperfusion injury (IRI) is of great interest.Here, we explored the molecular mechanisms underlying the protective effects of the SGLT2 inhibitor dapagliflozin (DAPA) against cardiac microvascular dysfunction mediated by IRI.Methods: DAPA effects were evaluated both in vivo, in mice subjected to IRI, and in vitro, in human coronary artery endothelial cells (HCAECs) exposed to hypoxia/reoxygenation (H/R).DAPA pretreatment attenuated luminal stenosis, endothelial swelling, and inflammation in cardiac microvessels of IRI-treated mice.Results: In H/R-challenged HCAECs, DAPA treatment improved endothelial barrier function, endothelial nitric oxide synthase (eNOS) activity, and angiogenic capacity, and inhibited H/R-induced apoptosis by preventing cofilin-dependent F-actin depolymerization and cytoskeletal degradation.Inhibition of H/R-induced xanthine oxidase (XO) activation and upregulation, sarco(endo)plasmic reticulum calcium-ATPase 2 (SERCA2) oxidation and inactivation, and cytoplasmic calcium overload was further observed in DAPA-treated HCAECs.DAPA also suppressed calcium/Calmodulin (CaM)-dependent kinase II (CaMKII) activation and cofilin phosphorylation, and preserved cytoskeleton integrity and endothelial cell viability following H/R.Importantly, the beneficial effects of DAPA on cardiac microvascular integrity and endothelial cell survival were largely prevented in IRI-treated SERCA2-knockout mice.Conclusions: These results indicate that DAPA effectively reduces cardiac microvascular damage and endothelial dysfunction during IRI through inhibition of the XO-SERCA2-CaMKII-cofilin pathway.