Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated Signaling

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 3; pp. 696 - 705
• Main Authors: Calvert, John W., Gundewar, Susheel, Jha, Saurabh, Greer, James J.M., Bestermann, William H., Tian, Rong, Lefer, David J.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2008
• Subjects: Adenylate Kinase - metabolism; AMP-Activated Protein Kinases; Animals; Biological and medical sciences; Blood Glucose - drug effects; Blood pressure; Cardiology. Vascular system; Care and treatment; Coronary heart disease; Coronary vessels; Diabetes; Diabetes Mellitus - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Gene Deletion; Gene Expression Regulation; Genetic aspects; Glucose; Health aspects; Heart; Hypoglycemic Agents - pharmacology; Ischemia; Ketamine; Kinases; Laboratory animals; Male; Medical sciences; Metformin; Metformin - pharmacology; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Multienzyme Complexes - metabolism; Myocardial Infarction - prevention & control; Myocarditis. Cardiomyopathies; Myocardium - pathology; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Oxidation; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proteins; Reperfusion Injury - complications; Research design; Signal Transduction - drug effects; Type 2 diabetes; Ventilators; Endocrinopathy; Myocardial infarction; Signal transduction; Biguanides; Diabetes mellitus; Cardiovascular disease; Metformin; Coronary heart disease; Myocardial disease
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db07-1098

Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated Signaling John W. Calvert 1 , Susheel Gundewar 1 , Saurabh Jha 1 , James J.M. Greer 1 , William H. Bestermann 2 , Rong Tian 3 and David J. Lefer 1 , 4 1 Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, New York 2 Vascular Medicine Center, Holston Medical Group, Kingsport, Tennessee 3 NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 4 Department of Pathology, Albert Einstein College of Medicine, Bronx, New York Address correspondence and reprint requests to David J. Lefer, PhD, Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: dlefer{at}aecom.yu.edu Abstract OBJECTIVE— Clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. The therapeutic effects of metformin have been reported to be mediated by its activation of AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase whose activation following myocardial ischemia has been suggested to be an endogenous protective signaling mechanism. We investigated the potential cardioprotective effects of a single, low-dose metformin treatment (i.e., 286-fold less than the maximum antihyperglycemic dose) in a murine model of myocardial ischemia-reperfusion (I/R) injury. RESEARCH DESIGN AND METHODS— Nondiabetic and diabetic ( db/db ) mice were subjected to transient myocardial ischemia for a period of 30 min followed by reperfusion. Metformin (125 μg/kg) or vehicle (saline) was administered either before ischemia or at the time of reperfusion. RESULTS— Administration of metformin before ischemia or at reperfusion decreased myocardial injury in both nondiabetic and diabetic mice. Importantly, metformin did not alter blood glucose levels. During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased endothelial nitric oxide (eNOS) phosphorylation at residue serine 1177. CONCLUSIONS— These findings provide important information that myocardial AMPK activation by metformin following I/R sets into motion events, including eNOS activation, which ultimately lead to cardioprotection. AAT, area at risk AMPK, AMP-activated protein kinase eNOS, endothelial nitric oxide FAO, fatty acid oxidation Inf, infarct size I/R, ischemia-reperfusion LCA, left coronary artery LVEDD, left ventricular end-diastolic diameter LVESD, left ventricular end-systolic diameter Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 14 December 2007. DOI: 10.2337/db07-1098. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received August 6, 2007. Accepted December 9, 2007. DIABETES