Chronic Empaglifozin treatment reduces myocardial infarct size in non-diabetic mice through STAT-3 mediated protection on microvascular endothelial cells and reduction of oxidative stress

Aims: Empagliflozin (EMPA) demonstrates cardioprotective effects on diabetic myocardium but its infarct sparing effects in normoglyceamia remain unspecified. We investigated the acute and chronic effect of EMPA on infarct size (IS) after ischemia- reperfusion injury (I/R) and the mechanisms of cardioprotection in non-diabetic mice. Results: Chronic oral administration of EMPA (6 weeks) reduced myocardial IS after 30min/2h I/R (29.5%±3.0 vs 45.8%±3.2 in the control group, p<0.01). Body weight, blood pressure, glucose levels and cardiac function remained unchanged between groups. Acute administration of EMPA 24h or 4h before I/R did not affect IS. Chronic EMPA treatment led to a significant reduction of oxidative stress biomarkers. STAT-3 was activated by Y(705) phosphorylation at the 10th min of R, but remained unchanged at 2h of R and in the acute administration protocols. Proteomic analysis was employed to investigate signaling intermediates and revealed that chronic EMPA treatment regulates several pathways at reperfusion including oxidative stress and integrin related proteins which were further evaluated. Superoxide dismutase and vascular endothelial growth factor were increased throughout reperfusion. EMPA pre-treatment (24h) increased the viability of Human Microvascular Endothelial Cells in normoxia and upon 3h hypoxia/1h reoxygenation and reduced reactive oxygen species production. In EMPA treated murine hearts, CD31/VEGFR2 positive endothelial cells and the pSTAT-3(Y705) signal derived from endothelial cells were boosted at early reperfusion. Innovation: Chronic EMPA administration reduces IS in healthy mice via STAT-3 pathway and increased survival of endothelial cells. Conclusion: Chronic but not acute administration of EMPA reduces IS through STAT-3 activation independently of diabetes mellitus.