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- and 
- Isoform Complexes in the Intact Ischemic Rat Heart
1 Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, United States
2 Department of Pediatrics, Baylor College of Medicine, Children's Nutrition Research Center, Houston, Texas, United States
3 Imperial College, London, United Kingdom
* To whom correspondence should be addressed. E-mail: lawrence.young{at}yale.edu.
AMP-activated protein kinase (AMPK) plays a key role in modulating cellular metabolic processes. AMPK is a heterotrimeric complex of 
catalytic, and 
and 
regulatory subunits that have multiple isoforms. Mutations in the cardiac 2 subunit have been associated with hypertrophic cardiomyopathy and pre-excitation syndromes. However, the physiologic regulation of AMPK complexes containing different subunit isoforms is not well defined and is important to understanding the function of this signaling pathway in the intact heart. We evaluated the kinase activity associated with heart AMPK complexes containing specific and AMPK isoforms in an in vivo rat model of regional ischemia. Left coronary occlusion activated immunoprecipitated 1 (6-fold, p<0.01) and 2 (9-fold, p<0.01) in the ischemic left ventricle (LV) compared to controls. The degree of activation depended on the extent of ischemia and paralleled echocardiographic contractile dysfunction. The 1 and 2 (not 3) regulatory subunits were expressed in the heart. The 1 and 2 subunits co-immunoprecipitated with 1 and 2 subunits in proportion to subunit content. 1 immunocomplexes accounted for 70% of the AMPK activity and AMPK Thr172 phosphorylation in control hearts. Ischemia similarly increased AMPK activity associated with the 1 and 2 complexes 3-fold (p<0.01 for each). Thus, both 1 and 2 AMPK catalytic subunits are activated by regional ischemia in vivo, irrespective of the 1 or 2 regulatory subunits to which they are complexed. Despite the pathophysiologic importance of 2 mutations, 1 complexes account for the predominance of AMPK activity in the ischemic heart.
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