title: A small molecule AMPK activator protects the heart against ischemia-reperfusion injury.
abstract: AMP-activated protein kinase (AMPK) is a stress signaling enzyme that orchestrates the regulation of energy-generating and -consuming pathways. Intrinsic AMPK activation protects the heart against ischemic injury and apoptosis, but whether pharmacologic AMPK stimulation mitigates ischemia-reperfusion damage is unknown. The aims of this study were to determine whether direct stimulation of AMPK using a small molecule activator, A-769662, attenuates myocardial ischemia-reperfusion injury and to examine its cardioprotective mechanisms. Isolated mouse hearts pre-treated with A-769662 had better recovery of left ventricular contractile function (55% vs. 29% of baseline rate-pressure product; p=0.03) and less myocardial necrosis (56% reduction in infarct size; p<0.01) during post-ischemic reperfusion compared to control hearts. Pre-treatment with A-769662 in vivo attenuated infarct size in C57Bl/6 mice undergoing left coronary artery occlusion and reperfusion compared to vehicle (36% vs. 18%, p=0.025). Mouse hearts with genetically inactivated AMPK were not protected by A-769662, indicating the specificity of this compound. Pre-treatment with A-769662 increased the phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2), preserved energy charge during ischemia, delayed the development of ischemic contracture, and reduced myocardial apoptosis and necrosis. A-769662 also augmented endothelial nitric oxide synthase (eNOS) activation during ischemia, which partially attenuated myocardial stunning, but did not prevent necrosis. AMPK is a therapeutic target that can be stimulated by a direct-acting small molecule in order to prevent injury during ischemia-reperfusion. The use of AMPK activators may represent a novel strategy to protect the heart and other solid organs against ischemia.
authors.affiliation: Yale University School of Medicine, Section of Cardiovascular Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
authors.forename: Agnes S
authors.initials: AS
authors.lastname: Kim
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Miller
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Wright
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.forename: Dake
authors.initials: D
authors.lastname: Qi
authors.forename: Kwame
authors.initials: K
authors.lastname: Atsina
authors.forename: Vlad
authors.initials: V
authors.lastname: Zaha
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents / Q000494:pharmacology*; D020536:Enzyme Activators / Q000494:pharmacology*; D006321:Heart / Q000503:physiopathology; D019194:Ischemic Preconditioning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D009336:Necrosis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D020536:Enzyme Activators; D020652:Peptide Elongation Factor 2; D011753:Pyrones; D013876:Thiophenes; D000255:Adenosine Triphosphate; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile