title: Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure.
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 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, 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-1alpha, in a murine model of heart failure.
authors.affiliation: Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Susheel
authors.initials: S
authors.lastname: Gundewar
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: Saurabh
authors.initials: S
authors.lastname: Jha
authors.forename: Iris
authors.initials: I
authors.lastname: Toedt-Pingel
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Ji
authors.forename: Denise
authors.initials: D
authors.lastname: Nunez
authors.forename: Arun
authors.initials: A
authors.lastname: Ramachandran
authors.forename: Mauricio
authors.initials: M
authors.lastname: Anaya-Cisneros
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010750:Phosphoproteins / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010750:Phosphoproteins; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C083557:p112 protein, rat; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D055372:AMP-Activated Protein Kinases