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(Circulation Research. 2008;103:1009.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Disruption of Sarcolemmal ATP-Sensitive Potassium Channel Activity Impairs the Cardiac Response to Systolic Overload

Xinli Hu, Xin Xu, Yimin Huang, John Fassett, Thomas P. Flagg, Ying Zhang, Colin G. Nichols, Robert J. Bache, Yingjie Chen

From the Cardiovascular Division (X.H., X.X., J.F., R.J.B., Y.C.) and Vascular Biology Center (X.H., X.X., Y.C.), Department of Medicine, University of Minnesota Medical School, Minneapolis; An Zhen Hospital (Y.H., Y.Z.), Beijing, China; and Cell Biology and Physiology (T.P.F., C.G.N.), Washington University School of Medicine, St Louis, Mo.

Correspondence to Yingjie Chen, MD, PhD, University of Minnesota, MMC 508, 420 Delaware St SE, Minneapolis, MN 55455. E-mail chenx106{at}umn.edu

Sarcolemmal ATP-sensitive potassium channels (K_ATP) act as metabolic sensors that facilitate adaptation of the left ventricle to changes in energy requirements. This study examined the mechanism by which K_ATP dysfunction impairs the left ventricular response to stress using transgenic mouse strains with cardiac-specific disruption of K_ATP activity (SUR1-tg mice) or Kir6.2 gene deficiency (Kir6.2 KO). Both SUR1-tg and Kir6.2 KO mice had normal left ventricular mass and function under unstressed conditions. Following chronic transverse aortic constriction, both SUR1-tg and Kir6.2 KO mice developed more severe left ventricular hypertrophy and dysfunction as compared with their corresponding WT controls. Both SUR1-tg and Kir6.2 KO mice had significantly decreased expression of peroxisome proliferator-activated receptor coactivator (PGC)-1 and a group of energy metabolism related genes at both protein and mRNA levels. Furthermore, disruption of K_ATP repressed expression and promoter activity of PGC-1 in cultured rat neonatal cardiac myocytes in response to hypoxia, indicating that K_ATP activity is required to maintain PGC-1 expression under stress conditions. PGC-1 gene deficiency also exacerbated chronic transverse aortic constriction–induced ventricular hypertrophy and dysfunction, suggesting that depletion of PGC-1 can worsen systolic overload induced ventricular dysfunction. Both SUR1-tg and Kir6.2 KO mice had decreased FOXO1 after transverse aortic constriction, in agreement with the reports that a decrease of FOXO1 can repress PGC-1 expression. Furthermore, inhibition of K_ATP caused a decrease of FOXO1 associated with PGC-1 promoter. These data indicate that K_ATP channels facilitate the cardiac response to stress by regulating PGC-1 and its target genes, at least partially through the FOXO1 pathway.

Key Words: ATP-sensitive potassium channels • cardiac hypertrophy • PGC-1