SGLT-2 inhibitor (dapagliflozin) protects against myocardial microcirculation injury induced by ischemia‒reperfusion through limiting NLRP3 inflammasome activation

Acute myocardial infarction represents a severe cardiovascular ailment that poses a significant threat to human health. Although reperfusion therapy following acute myocardial infarction can restore blood circulation, it has the potential to induce myocardial ischemia-reperfusion injury. Clinical trials have indicated that dapagliflozin can reduce the risk of heart failure progression or cardiovascular-related death and alleviate microvascular damage during cardiac ischemia/reperfusion injury. By integrating animal models, experimental analyses, and hemodynamic simulations, this study comprehensively explored the impact and underlying mechanisms of dapagliflozin in ameliorating microcirculation reperfusion injury from multiple aspects. These findings demonstrated that dapagliflozin mitigated myocardial microcirculation reperfusion injury caused by ischemia‒reperfusion. Mechanistically, dapagliflozin inhibited the secretion of CXCL1 and CXCL8 by suppressing the production of IL-1β, which was triggered by the activation of the NLRP3 inflammasome. This, in turn, improved NLRP3 inflammasome-mediated mitochondrial dysfunction. Additionally, dapagliflozin attenuated the decrease in microvascular density and the number of microvascular branches in the cardiac microcirculation by downregulating NLRP3 expression. These findings suggest that dapagliflozin may promote the regeneration of cardiac microvascular branches by inhibiting NLRP3 inflammasome activation, thereby reversing the abnormal cardiac hemodynamic changes induced by myocardial ischemia–reperfusion. In summary, this research provides a theoretical basis for the use of dapagliflozin in preventing perioperative ischemia‒reperfusion injury in patients with acute myocardial infarction.