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

作者：Susheel Gundewar, John W. Calvert, Saurabh Kumar Jha, Iris Toedt‐Pingel, Sang Yong Ji, Denise Nunez, Arun Ramachandran, Mauricio Anaya-Cisneros, Rong Tian, David J. Lefer · 发表于：Circulation Research · 年份：2008 · DOI：10.1161/circresaha.108.190918 · 被引用次数：422 · 研究领域：Metabolism, Diabetes, and Cancer、Cardiovascular Function and Risk Factors、Pancreatic function and diabetes

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 microg/kg) administered to mice at ischemia and then daily improved survival by 47% (P<0.05 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 (P<0.01 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 proliferator-activated receptor-gamma coactivator (PGC)-1alpha expression in cardiac myocytes. Furthermore, me...