Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload.
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 gamma coactivator (PGC)-1alpha 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-1alpha in cultured rat neonatal cardiac myocytes in response to hypoxia, indicating that K(ATP) activity is required to maintain PGC-1alpha expression under stress conditions. PGC-1alpha gene deficiency also exacerbated chronic transverse aortic constriction-induced ventricular hypertrophy and dysfunction, suggesting that depletion of PGC-1alpha 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-1alpha expression. Furthermore, inhibition of K(ATP) caused a decrease of FOXO1 associated with PGC-1alpha promoter. These data indicate that K(ATP) channels facilitate the cardiac response to stress by regulating PGC-1alpha and its target genes, at least partially through the FOXO1 pathway.
Hu
Xinli
X
Cardiovascular Division, Department of Medicine, Universityof Minnesota Medical School, Minneapolis, MN 55455, USA.
Xu
Xin
X
Huang
Yimin
Y
Fassett
John
J
Flagg
Thomas P
TP
Zhang
Ying
Y
Nichols
Colin G
CG
Bache
Robert J
RJ
Chen
Yingjie
Y
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000601:surgery; D001483:Base Sequence; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003250:Constriction; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000503:physiopathology; D054086:KATP Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D012720:Severity of Illness Index; D064233:Sulfonylurea Receptors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D054086:KATP Channels; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D000099161:Kcnj11 Channel; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat; C467200:Foxo1 protein, mouse; C485290:Ppargc1a protein, mouse
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