Abstract
Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy (DCM). This study was designed to determine the effect of an antioxidant butin (BUT) on ischemia/reperfusion-induced myocardial injury in diabetic mice. Myocardial ischemia/reperfusion (MI/R) was induced in C57/BL6J diabetes mice. Infarct size and cardiac function were detected. For in vitro study, H9c2 cells were used. To clarify the mechanisms, proteases inhibitors or siRNA were used. Proteins levels were investigated by Western blotting. In diabetes MI/R model, BUT significantly alleviated myocardial infarction and improved heart function, together with prevented diabetes-induced cardiac oxidative damage. The expression of Nrf2, AMPK, AKT and GSK-3β were significantly increased by BUT. Furthermore, in cultured H9c2 cardiac cells silencing Nrf2 gene with its siRNA abolished the BUT’s prevention of I/R-induced myocardial injury. Inhibition of AMPK and AKT signaling by relative inhibitor or specific siRNA decreased the level of BUT-induced Nrf2 expression, and diminished the protective effects of BUT. The interplay relationship between GSK-3β and Nrf2 was also verified with relative overexpression and inhibitors. Our findings indicated that BUT protected against I/R-induced ROS-mediated apoptosis by upregulating the AMPK/Akt/GSK-3β pathway, which further activated Nrf2-regulated antioxidant enzymes in diabetic cardiomyocytes exposed to I/R.
Highlights
Improving antioxidant enzyme activities and suppressing oxidative stress, are appropriate targets in treating diabetes-induced cardiovascular disease
Nrf[2] is a nuclear transcription factor that binds to antioxidant-response element (ARE) and regulates expression and coordinated induction of a battery of chemoprotective genes in response to antioxidants, oxidants, and radiations, including NAD (P) H: quinine oxidoreductase 1 (NQO1), NRH: quinone oxidoreductase 2 (NQO2), glutathione S-transferase Ya subunit (GST Ya Subunit), heme oxygenase 1 (HO-1), and γ-glutamylcysteine synthetase (γ-GCS), known as glutamate cysteine ligase (GCL)[6]
In BUT and MET treatment group, LVDP, +LV dP/dt max and LV dP/dtmin were improved significantly at the end of reperfusion when compared with diabetes mellitus (DM) +ischemia and reperfusion (I/R) group
Summary
Improving antioxidant enzyme activities and suppressing oxidative stress, are appropriate targets in treating diabetes-induced cardiovascular disease. Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that has versatile biological functions in cells, including regulation of metabolism, cell growth/death, and gene transcription[8]. Both GSK-3αand GSK-3βappear to be important in certain aspects, GSK-3αhas a more critical role in regulating hepatic glucose metabolism and insulin sensitivity, and GSK-3βis the predominant regulator of glycogen synthase, Wnt signaling and sensitization to apoptosis[9]. We performed this study to determine whether BUT protected against experimental diabetic cardiomyocytes which exposed to I/R in vitro and in vivo via AMPK/Akt/GSK-3β/Nrf[2] signaling pathway
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