Τίτλος:
Empagliflozin limits myocardial infarction in vivo and cell death in vitro: Role of STAT3, mitochondria, and redox aspects
Περίληψη:
Empagliflozin (EMPA), a drug approved for type 2 diabetes management, reduced cardiovascular death but is unknown if it reduces myocardial infarction. We sought to investigate: (i) the effect of EMPA on myocardial function and infarct size after ischemia/reperfusion in mice fed with western diet (WD), (ii) the underlying signaling pathways, (iii) its effects on cell survival in rat embryonic-heart-derived cardiomyoblasts (H9C2) and endothelial cells (ECs). To facilitate the aforementioned aims, mice were initially randomized in Control and EMPA groups and were subjected to 30 min ischemia and 2 h reperfusion. EMPA reduced body weight, blood glucose levels, and mean arterial pressure. Cholesterol, triglyceride, and AGEs remained unchanged. Left ventricular fractional shortening was improved (43.97 ± 0.92 vs. 40.75 ± 0.61%) and infarct size reduced (33.2 ± 0.01 vs. 17.6 ± 0.02%). In a second series of experiments, mice were subjected to the above interventions up to the 10th min of reperfusion and myocardial biopsies were obtained for assessment of the signaling cascade. STAT3 was increased in parallel with reduced levels of malondialdehyde (MDA) and reduced expression of myocardial iNOS and interleukin-6. Cell viability and ATP content were increased in H9C2 and in ECs. While, STAT3 phosphorylation is known to bestow infarct sparing properties through interaction with mitochondria, we observed that EMPA did not directly alter the mitochondrial calcium retention capacity (CRC); therefore, its effect in reducing myocardial infarction is STAT3 dependent. In conclusion, EMPA improves myocardial function and reduces infarct size as well as improves redox regulation by decreasing iNOS expression and subsequently lipid peroxidation as shown by its surrogate marker MDA. The mechanisms of action implicate the activation of STAT3 anti-oxidant and anti-inflammatory properties. © 2017 Andreadou, Efentakis, Balafas, Togliatto, Davos, Varela, Dimitriou, Nikolaou, Maratou, Lambadiari, Ikonomidis, Kostomitsopoulos, Brizzi, Dimitriadis and Iliodromitis.
Συγγραφείς:
Andreadou, I.
Efentakis, P.
Balafas, E.
Togliatto, G.
Davos, C.H.
Varela, A.
Dimitriou, C.A.
Nikolaou, P.-E.
Maratou, E.
Lambadiari, V.
Ikonomidis, I.
Kostomitsopoulos, N.
Brizzi, M.F.
Dimitriadis, G.
Iliodromitis, E.K.
Λέξεις-κλειδιά:
adenosine triphosphate; advanced glycation end product; calcium; cholesterol; empagliflozin; glucose; hydroxymethylglutaryl coenzyme A reductase kinase; hydroxymethylglutaryl coenzyme A reductase kinase alpha; inducible nitric oxide synthase; interleukin 6; malonaldehyde; STAT3 protein; triacylglycerol; unclassified drug, animal experiment; animal model; animal tissue; antiinflammatory activity; antioxidant activity; Article; calcium retention capacity; cardiovascular parameters; cell death; cell hypoxia; cell survival; cell viability; cholesterol blood level; controlled study; drug efficacy; drug mechanism; endothelium cell; glucose blood level; H9c2(2-1) cell line; heart function; heart infarction; heart infarction size; heart left ventricle fractional shortening; heart mitochondrion; heart muscle biopsy; heart muscle ischemia; heart muscle reperfusion; heart protection; in vitro study; in vivo study; lipid peroxidation; male; mean arterial pressure; mitochondrial permeability; mouse; nonhuman; oxidation reduction state; protein analysis; protein expression; protein function; signal transduction; treatment duration; triacylglycerol blood level; weight reduction; Western diet
