The role of AMP-activated protein kinase in myocardial tolerance to ischemia and reperfusion injury in type 2 diabetes mellitus and its relation to metformin therapy
Background. Several previous studies suggest that the drug in the biguanide class — metformin, in addition to the well-known hypoglycemic action can exert a significant cardioprotective effect. Molecular mechanisms of cardioprotection mediated by metformin are practically unknown. Objective. To examine the role of AMP-activated protein kinase (AMPK) — a key regulator of energy metabolism in myocardial tolerance to ischemia and reperfusion injury under the action of metformin in animals with type 2 diabetes mellitus (T2DM). Design and methods. The Wistar rats with streptozotocin-induced neonatal type 2 diabetes mellitus were used in the study. Ischemia-reperfusion of the myocardium was modeled according to Langendorf on the isolated heart with the preliminary intraperitoneal administration of metformin for 3 days. Cardioprotective effect of metformin was assessed by hemodynamic parameters and the size of myocardial infarction. AMPK activity in the myocardium was assessed by Western blot analysis. Results. Metformin did not significantly affected infarct size and nature of the postischemic recovery of left ventricular function in control group and in animals with T2DM. At the same time, the infarct size in T2DM was significantly lower than in the controls, which confirms the phenomenon of metabolic preconditioning. Activation of AMPK in the myocardium compared with the control group was observed in animals with T2DM, and in both metformin groups. Administration of metformin to animals with T2DM was accompanied by the maximum increase in AMPK activity. Conclusions. T2DM led to the activation of AMPK and was accompanied by improved myocardial tolerance to ischemia. In the absence of significant cardioprotective effect pre-ischemic systemic administration of metformin led to the increase of AMPK activity in the myocardium that was the highest in the animals with T2DM and metformin administration.