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: Agnes S Kim, Edward J Miller, Tracy M Wright, Ji Li, Dake Qi, Kwame Atsina, Vlad Zaha, Kei Sakamoto, Lawrence H Young
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 51 Issue 1 Pg. 24-32 (Jul 2011) ISSN: 1095-8584 [Electronic] England
• PMID: 21402077 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Biphenyl Compounds
• Cardiotonic Agents
• Enzyme Activators
• Peptide Elongation Factor 2
• Pyrones
• Thiophenes
• Adenosine Triphosphate
• Nitric Oxide Synthase Type III
• AMP-Activated Protein Kinases
• 4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Apoptosis (drug effects)
• Biphenyl Compounds
• Cardiotonic Agents (pharmacology)
• Enzyme Activators (pharmacology)
• Heart (physiopathology)
• Ischemic Preconditioning
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardial Infarction (drug therapy, pathology)
• Myocardial Reperfusion Injury (drug therapy, prevention & control)
• Necrosis
• Nitric Oxide Synthase Type III (metabolism)
• Peptide Elongation Factor 2 (metabolism)
• Pyrones (pharmacology)
• Thiophenes (pharmacology)