Metformin attenuates myocardial ischemia-reperfusion injury via up-regulation of antioxidant enzymes

The objective was to examine the protective effect of metformin (Met) on myocardial ischemia-reperfusion (IR) injury and whether the mechanism was related to the AMPK/ antioxidant enzymes signaling pathway. Rat Langendorff test and H(2)O(2)-treated rat cardiomyocytes (H9c2) were used in this study. Met treatment significantly improved left ventricular (LV) function, reduced infarct size and CK-MB release in comparison with IR group. Decreased TUNEL staining positive cells were also observed in IR+Met group ex vivo. Met treatment markedly inhibited IR inducing cell death and significantly decreased apoptosis with few generations of reactive oxygen species (ROS) in H9c2 cells in comparison with IR group. Up-regulated expressions of phosphorylated LKB1/AMPK/ACC, as well as down-regulated expressions of apoptotic proteins (Bax and cleaved caspase 3) were found in IR+Met group when compared to the IR group. Importantly, Met significantly up-regulated the expression of antioxidant enzymes (MnSOD and catalase) during IR procedure either ex vivo or in vitro. Compound C, a conventional inhibitor of AMPK, abolished the promoting effect of Met on antioxidant enzymes, and then attenuated the protective effect of Met on IR injury in vitro. In conclusion, Met exerted protective effect on myocardial IR injury, and this effect was AMPK/ antioxidant enzymes dependent.