Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure

Abstract

Abstract-Clinical studies have reported that the widely used antihyperglycemic drug metformin significantly reduces cardiac risk factors and improves clinical outcomes in patients with heart failure. The mechanisms by which metformin exerts these cardioprotective effects remain unclear and may be independent of antihyperglycemic effects. We tested the hypothesis that chronic activation of AMP-activated protein kinase (AMPK) with low-dose metformin exerts beneficial effects on cardiac function and survival in in vivo murine models of heart failure. Mice were subjected to permanent left coronary artery occlusion or to 60 minutes left coronary artery occlusion followed by reperfusion for 4 weeks. High-resolution, 2D echocardiography was performed at baseline and 4 weeks after myocardial infarction to assess left ventricular dimensions and function. Metformin (125 g/kg) administered to mice at ischemia and then daily improved survival by 47% (PϽ0.05 versus vehicle) at 4 weeks following permanent left coronary artery occlusion. Additionally, metformin given at reperfusion and then daily preserved left ventricular dimensions and left ventricular ejection fraction (PϽ0.01 versus vehicle) at 4 weeks. The improvement in cardiac structure and function was associated with increases in AMPK and endothelial nitric oxide synthase (eNOS) phosphorylation, as well as increased peroxisome proliferatoractivated receptor-␥ coactivator (PGC)-1␣ expression in cardiac myocytes. Furthermore, metformin significantly improved myocardial cell mitochondrial respiration and ATP synthesis compared to vehicle. The cardioprotective effects of metformin were ablated in mice lacking functional AMPK or eNOS. This study demonstrates that metformin significantly improves left ventricular function and survival via activation of AMPK and its downstream mediators, eNOS and PGC-1␣, in a murine model of heart failure. Key Words: myocardial ischemia Ⅲ heart failure Ⅲ metformin Ⅲ nitric oxide H eart failure (HF) is the inability of the heart to meet hemodynamic demands and represents the end stage of various forms of cardiac disease. In the industrialized nations, HF represents a major health problem that has been increasing in prevalence and incidence. In the United States, HF affects more than 5 million people, with 500 000 new cases reported every year. It is responsible for almost 1 million hospital admissions and 40 000 deaths annually. 1 The most important cause of HF is coronary artery disease and acute myocardial infarction, leading to loss of functioning myocytes, development of myocardial fibrosis, and subsequent left ventricular (LV) remodeling, all of which contribute toward the development of LV dysfunction.Metformin is an orally administered biguanide drug that is widely used to lower blood glucose concentrations in patients with diabetes mellitus. Metformin decreases blood glucose by mechanisms different from those of sulfonylureas or insulin and exerts its actions by enhancing insulin sensitivity, inducing greater peripheral uptake of glu...

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