SGLT2i protects against myocardial I/R-induced coronary microvascular injury by inhibiting glycocalyx degradation

Ischemic heart disease remains a global health challenge. Current treatments for ischemia can trigger myocardial ischemia/reperfusion (I/R) injury. Despite extensive research, there is still a lack of integrated research between basic and clinical studies on the mechanisms and interventions of I/R injury. This study aimed to integrate preclinical and clinical evidence to identify therapeutic candidates for I/R injury and elucidate underlying mechanisms. Target-disease association and transcriptomic profiling were combined to prioritize an approved drug target for I/R injury, which identified sodium‑glucose cotransporter 2(SGLT2). The cardioprotective effect of SGLT2i was evaluated using two‑sample Mendelian randomization (MR) and a murine I/R model, with coronary microvascular structure and function assessed by transmission electron microscopy and immunofluorescence. A retrospective clinical cohort was used to examine the association between SGLT2i and angiography-derived microcirculatory resistance in patients undergoing percutaneous coronary intervention (PCI). The effect of SGLT2i on the endothelial glycocalyx, the first barrier of blood vessels, was further validated in vivo. Mediation MR was performed to examine whether glycocalyx‑degrading enzymes (GDEs) mediate the association between genetically proxied SGLT2 inhibition and MI risk in humans. Integrated target-disease and transcriptomic analyses identified SGLT2i as a therapeutic candidate for I/R injury, and preclinical experiments confirmed that SGLT2i markedly attenuated I/R‑induced myocardial damage. Mechanistically, SGLT2i exerted cardioprotective effects by preserving coronary microvascular function. Furthermore, SGLT2i preserved coronary microvascular function by preventing microvascular glycocalyx degradation. In line with the mechanism, SGLT2i’s cardioprotective effects were significantly weakened upon exogenous GDE administration. Notably, our clinical evidence further supported these preclinical findings. MR analyses provided genetic evidence of an association between genetically proxied SGLT2 inhibition and myocardial infarction risk. In post-PCI patients, SGLT2i was associated with improved coronary microvascular function. Mediation MR further identified neuraminidase 1, a key GDE, as a potential mediator of SGLT2 inhibition and MI risk in humans. Integrated preclinical, clinical, and human‑genetic analyses provide complementary evidence that SGLT2i is associated with microvascular protection after I/R, with glycocalyx preservation as a potential contributor. Our findings highlight the pivotal role of microvascular glycocalyx in I/R pathogenesis, complementing other known cardioprotective effects of SGLT2i.