A small molecule AMPK activator protects the heart against ischemia-reperfusion injury

Agnes S. Kim, Edward J. Miller, Tracy Wright, Ji Li, Dake Qi, Kwame Atsina, Vlad Zaha, Kei Sakamoto, Lawrence H. Young

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)24-32
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume51
Issue number1
DOIs
StatePublished - Jul 2011
Externally publishedYes

Fingerprint

A 769662
AMP-Activated Protein Kinases
Reperfusion Injury
Ischemia
Necrosis
Ischemic Contracture
Peptide Elongation Factor 2
Apoptosis
Myocardial Stunning
Myocardial Reperfusion Injury
Myocardial Reperfusion
Nitric Oxide Synthase Type III
Coronary Occlusion
Left Ventricular Function
Reperfusion
Myocardial Ischemia
Coronary Vessels
Phosphorylation
Pressure

Keywords

  • AMPK
  • Cardioprotection
  • Ischemic preconditioning
  • Reperfusion injury
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

A small molecule AMPK activator protects the heart against ischemia-reperfusion injury. / Kim, Agnes S.; Miller, Edward J.; Wright, Tracy; Li, Ji; Qi, Dake; Atsina, Kwame; Zaha, Vlad; Sakamoto, Kei; Young, Lawrence H.

In: Journal of Molecular and Cellular Cardiology, Vol. 51, No. 1, 07.2011, p. 24-32.

Research output: Contribution to journalArticle

Kim, AS, Miller, EJ, Wright, T, Li, J, Qi, D, Atsina, K, Zaha, V, Sakamoto, K & Young, LH 2011, 'A small molecule AMPK activator protects the heart against ischemia-reperfusion injury', Journal of Molecular and Cellular Cardiology, vol. 51, no. 1, pp. 24-32. https://doi.org/10.1016/j.yjmcc.2011.03.003
Kim, Agnes S. ; Miller, Edward J. ; Wright, Tracy ; Li, Ji ; Qi, Dake ; Atsina, Kwame ; Zaha, Vlad ; Sakamoto, Kei ; Young, Lawrence H. / A small molecule AMPK activator protects the heart against ischemia-reperfusion injury. In: Journal of Molecular and Cellular Cardiology. 2011 ; Vol. 51, No. 1. pp. 24-32.
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