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Am J Physiol Heart Circ Physiol 291: H1927-H1934, 2006. First published April 28, 2006; doi:10.1152/ajpheart.00251.2006
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Activation of AMPK {alpha}- and {gamma}-isoform complexes in the intact ischemic rat heart

Ji Li,1 David L. Coven,1 Edward J. Miller,1 Xiaoyue Hu,1 Martin E. Young,2 David Carling,3 Albert J. Sinusas,1 and Lawrence H. Young1

1Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; 2Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas; and 3Cellular Stress Group, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom

Submitted 10 March 2006 ; accepted in final form 26 April 2006

AMP-activated protein kinase (AMPK) plays a key role in modulating cellular metabolic processes. AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic {alpha}-subunits and regulatory beta- and {gamma}-subunits with multiple isoforms. Mutations in the cardiac {gamma}2-isoform have been associated with hypertrophic cardiomyopathy and pre-excitation syndromes. However, physiological regulation of AMPK complexes containing different subunit isoforms is not well defined and is important for an understanding of the function of this signaling pathway in the intact heart. We evaluated the kinase activity associated with heart AMPK complexes containing specific {alpha}- and {gamma}-subunit isoforms of AMPK in an in vivo rat model of regional ischemia. Left coronary artery occlusion activated the immunoprecipitated {alpha}1-isoform (6-fold, P < 0.01) and {alpha}2-isoform (9-fold, P < 0.01) in the ischemic left ventricle compared with sham controls. The degree of {alpha}-subunit activation depended on the extent of ischemia and paralleled echocardiographic contractile dysfunction. The regulatory {gamma}1- and {gamma}2-isoforms were expressed in the heart. The {gamma}1- and {gamma}2-isoforms coimmunoprecipitated with {alpha}1- and {alpha}2-isoforms in proportion to {alpha}-subunit content. {gamma}1-Isoform immunocomplexes accounted for 70% of AMPK activity and AMPK phosphorylation (Thr172) in hearts. Ischemia similarly increased AMPK activity associated with the {gamma}1- and {gamma}2-isoform complexes threefold (P < 0.01 for each). Thus AMPK catalytic {alpha}1- and {alpha}2-isoforms are activated by regional ischemia in vivo in the heart, irrespective of the regulatory {gamma}1- or {gamma}2-isoforms to which they are complexed. Despite the pathophysiological importance of {gamma}2-isoform mutations, {gamma}1-isoform complexes account for most of the AMPK activity in the ischemic heart.

adenosine monophosphate-activated protein kinase; ischemia; subunits; isoforms


Address for reprint requests and other correspondence: L. H. Young, Section of Cardiovascular Medicine, 3 FMP, Yale Univ. School of Medicine, 333 Cedar St., New Haven, CT 06520-8017 (e-mail: lawrence.young{at}yale.edu)




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