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

Abstract

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 H2O2-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.

Metformin decreases testicular damages following ischaemia/reperfusion injury in rats

“…Combination of three contributory factors: increased antioxidant enzyme activity, lower mitochondrial ROS production and reduction of post-ischaemic inflammation have been suggested as mechanisms of metformin action to ameliorate I/R damage (Cahova et al, 2015). Recently, metformin has been proposed to exert its protective effect through the AMPK/ antioxidant enzymes signalling pathway (Wang et al, 2017). Recently, metformin has been proposed to exert its protective effect through the AMPK/ antioxidant enzymes signalling pathway (Wang et al, 2017).…”

“…Ge et al (2017) demonstrated that Akt-mediated down-regulation of the phosphorylation of JNK3 signalling pathway contributed to the protection provided by metformin in hippocampus against ischaemic damage related to I/R injury. Recently, metformin has been proposed to exert its protective effect through the AMPK/ antioxidant enzymes signalling pathway (Wang et al, 2017). A number of reports also support the cardioprotective effect of metformin against myocardial infarction through AMPK-eNOS-mediated signalling pathway (Calvert et al, 2007) and adenosine receptor activation (Paiva et al, 2009).…”

“…Also, it has been demonstrated that metformin lowered inflammation and suppressed apoptosis in renal tubular epithelial cells in rats after renal I/R (Wang et al, 2017) by increasing the energy supply to the ischaemic tissue. Also, it has been demonstrated that metformin lowered inflammation and suppressed apoptosis in renal tubular epithelial cells in rats after renal I/R (Wang et al, 2017) by increasing the energy supply to the ischaemic tissue.…”

“…Metformin, an insulin sensitiser that decreases hepatic glucose output and increases peripheral glucose uptake, has been commonly used in the treatment of type 2 diabetes mellitus. Also, it has been demonstrated that metformin lowered inflammation and suppressed apoptosis in renal tubular epithelial cells in rats after renal I/R (Wang et al, 2017) by increasing the energy supply to the ischaemic tissue. Metformin is mostly brought into cells by active transport and functions by inhibiting the activity of the mitochondrial respiratory chain (Owen, Doran, & Halestrap, 2000) and activating the AMP-activated protein kinase (AMPK; Zhou et al, 2001).…”

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance

“…C. elegans AMPK responds to nutritional state and coordinates hypoxia resistance (LaRue 101 and Padilla, 2011). These results translate to mammalian models, as AMPK protects against hypoxic 102 pathologies like ischemic reperfusion injury (Wang et al, 2017, Kim et al, 2011. In addition, AMPK acts as a 103 neuronal energy sensor capable of changing an animal's behavior based on food availability (Ahmadi and Roy, 104 2016, Yurgel et al, 2019).…”