Protective effect of butin against ischemia/reperfusion-induced myocardial injury in diabetic mice: involvement of the AMPK/GSK-3β/Nrf2 signaling pathway

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.

Tea polyphenols protect bovine mammary epithelial cells from hydrogen peroxide-induced oxidative damage in vitro by activating NFE2L2/HMOX1 pathways

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The role of sodium hydrosulfide in attenuating the aging process via PI3K/AKT and CaMKKβ/AMPK pathways

“…5a, b, c). In recent studies that aligned with our results, the AMPK and PI3K/AKT pathways were reportedly involved in the regulation of antioxidant activity in oxidative stress models induced by ischemia/reperfusion in mice or H 2 O 2 in Leydig's cells [62], [63]. In our study, antioxidant enzymes such as PRDX2 and TXNRD1 changed in a similar pattern as the activity of the antioxidants mentioned above in vivo and in vitro (Fig.…”

Farrerol Directly Targets GSK-3β to Activate Nrf2-ARE Pathway and Protect EA.hy926 Cells against Oxidative Stress-Induced Injuries

“…Ser9 without affecting the protein expression of GSK-3β and enhanced Nrf2 nuclear translocation in PC12 cells, H9c2 cells, and L02 cells, respectively [36,40,43]. This confirms that GSK-3β participates in farrerol-mediated endothelial cytoprotective effects and upregulation of the Nrf2-ARE signaling pathway.…”