Chronic Empagliflozin Treatment Reduces Myocardial Infarct Size in Nondiabetic Mice Through STAT-3-Mediated Protection on Microvascular Endothelial Cells and Reduction of Oxidative Stress.
Empagliflozin (EMPA) demonstrates cardioprotective effects on diabetic myocardium but its infarct-sparing effects in normoglycemia remain unspecified. We investigated the acute and chronic effect of EMPA on infarct size after ischemia-reperfusion (I/R) injury and the mechanisms of cardioprotection in nondiabetic mice.  Chronic oral administration of EMPA (6 weeks) reduced myocardial infarct size after 30 min/2 h I/R (26.5% ± 3.9% vs 45.8% ± 3.3% in the control group, p < 0.01). Body weight, blood pressure, glucose levels, and cardiac function remained unchanged between groups. Acute administration of EMPA 24 or 4 h before I/R did not affect infarct size. Chronic EMPA treatment led to a significant reduction of oxidative stress biomarkers. STAT-3 (signal transducer and activator of transcription 3) was activated by Y(705) phosphorylation at the 10th minute of R, but it remained unchanged at 2 h 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 that were further evaluated. Superoxide dismutase and vascular endothelial growth factor were increased throughout reperfusion. EMPA pretreatment (24 h) increased the viability of human microvascular endothelial cells in normoxia and on 3 h hypoxia/1 h 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.  Chronic EMPA administration reduces infarct size in healthy mice via the STAT-3 pathway and increases the survival of endothelial cells.  Chronic but not acute administration of EMPA reduces infarct size through STAT-3 activation independently of diabetes mellitus.
['Nikolaou|Panagiota Efstathia|PE|', 'Efentakis|Panagiotis|P|', 'Abu Qourah|Fairouz|F|', 'Femminò|Saveria|S|', 'Makridakis|Manousos|M|', 'Kanaki|Zoi|Z|', 'Varela|Aimilia|A|', 'Tsoumani|Maria|M|', 'Davos|Constantinos H|CH|', 'Dimitriou|Constantinos A|CA|', 'Tasouli|Androniki|A|', 'Dimitriadis|George|G|', 'Kostomitsopoulos|Nikolaos|N|', 'Zuurbier|Coert J|CJ|', 'Vlahou|Antonia|A|', 'Klinakis|Apostolos|A|', 'Brizzi|Maria F|MF|', 'Iliodromitis|Efstathios K|EK|', 'Andreadou|Ioanna|I|']
D000284:Administration, Oral D000818:Animals D001559:Benzhydryl Compounds D002316:Cardiotonic Agents D015687:Cell Hypoxia D042783:Endothelial Cells D005960:Glucosides D006801:Humans D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D055806:Microvessels D009203:Myocardial Infarction D010084:Oxidation-Reduction D018384:Oxidative Stress D050796:STAT3 Transcription Factor
empagliflozin infarct size normoglycemia SGLT2 inhibitors