Τίτλος:
Chronic Empagliflozin Treatment Reduces Myocardial Infarct Size in Nondiabetic Mice through STAT-3-Mediated Protection on Microvascular Endothelial Cells and Reduction of Oxidative Stress
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Aims: 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. Results: 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. Innovation: Chronic EMPA administration reduces infarct size in healthy mice via the STAT-3 pathway and increases the survival of endothelial cells. Conclusion: Chronic but not acute administration of EMPA reduces infarct size through STAT-3 activation independently of diabetes mellitus. © Copyright 2021, Mary Ann Liebert, Inc., publishers 2021.
Συγγραφείς:
Nikolaou, P.E.
Efentakis, P.
Abu Qourah, F.
Femminò, S.
Makridakis, M.
Kanaki, Z.
Varela, A.
Tsoumani, M.
Davos, C.H.
Dimitriou, C.A.
Tasouli, A.
Dimitriadis, G.
Kostomitsopoulos, N.
Zuurbier, C.J.
Vlahou, A.
Klinakis, A.
Brizzi, M.F.
Iliodromitis, E.K.
Andreadou, I.
Περιοδικό:
Antioxidants and Redox Signaling
Εκδότης:
MARY ANN LIEBERT INC PUBL
Λέξεις-κλειδιά:
benzhydryl derivative; cardiotonic agent; empagliflozin; glucoside; STAT3 protein; Stat3 protein, mouse, animal; C57BL mouse; cell hypoxia; drug effect; endothelium cell; heart infarction; human; male; metabolism; microvasculature; mouse; oral drug administration; oxidation reduction reaction; oxidative stress, Administration, Oral; Animals; Benzhydryl Compounds; Cardiotonic Agents; Cell Hypoxia; Endothelial Cells; Glucosides; Humans; Male; Mice; Mice, Inbred C57BL; Microvessels; Myocardial Infarction; Oxidation-Reduction; Oxidative Stress; STAT3 Transcription Factor
DOI:
10.1089/ars.2019.7923
