Published online before print December 18, 2008, doi: 10.1161/CIRCRESAHA.108.190918
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2009 American Heart Association, Inc.
Integrative Physiology |
Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure
From the Department of Medicine (S.G., J.W.C., S.J., I.T.-P., S.Y.J., D.N., A.R., M.A.-C., D.J.L.), Division of Cardiology; and Department of Pathology (D.J.L.), Albert Einstein College of Medicine, Bronx, NY; and Nuclear Magnetic Resonance Laboratory for Physiological Chemistry (R.T.), Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to David J. Lefer, PhD, Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, Crawford Long Hospital, 550 Peachtree St NE, Atlanta, GA 30308. E-mail dlefer{at}emory.edu
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 µg/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-
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 • heart failure • metformin • nitric oxide
Related Article:
Circ. Res. 2009 104: 282-284.
This article has been cited by other articles:
 |
|
 |
|
  R Khurana and I S Malik Metformin: safety in cardiac patients Heart, January 15, 2010; 96(2): 99 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Opie and J. Knuuti The adrenergic-Fatty Acid load in heart failure. J. Am. Coll. Cardiol., October 27, 2009; 54(18): 1637 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Kewalramani, P. Puthanveetil, F. Wang, M. S. Kim, S. Deppe, A. Abrahani, D. S. Luciani, J. D. Johnson, and B. Rodrigues AMP-activated protein kinase confers protection against TNF-{alpha}-induced cardiac cell death Cardiovasc Res, October 1, 2009; 84(1): 42 - 53. [Abstract] [Full Text] [PDF]
|
|