RGD Reference Report - Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload. - Rat Genome Database

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Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload.

Authors: Hu, X  Xu, X  Huang, Y  Fassett, J  Flagg, TP  Zhang, Y  Nichols, CG  Bache, RJ  Chen, Y 
Citation: Hu X, etal., Circ Res. 2008 Oct 24;103(9):1009-17. doi: 10.1161/CIRCRESAHA.107.170795. Epub 2008 Sep 18.
RGD ID: 7297042
Pubmed: PMID:18802029   (View Abstract at PubMed)
PMCID: PMC2877276   (View Article at PubMed Central)
DOI: DOI:10.1161/CIRCRESAHA.107.170795   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Left Ventricular Hypertrophy  ISOKcnj11 (Mus musculus)7297042; 7297042 RGD 
Left Ventricular Hypertrophy  IMP 7297042 RGD 
Left Ventricular Hypertrophy  ISOPpargc1a (Mus musculus)7297042; 7297042mRNA:increased expression:heart (mouse)RGD 
Left Ventricular Hypertrophy  IEP 7297042mRNA:increased expression:heart (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Kcnj11  (potassium inwardly-rectifying channel, subfamily J, member 11)
Ppargc1a  (PPARG coactivator 1 alpha)

Genes (Mus musculus)
Kcnj11  (potassium inwardly rectifying channel, subfamily J, member 11)
Ppargc1a  (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha)

Genes (Homo sapiens)
KCNJ11  (potassium inwardly rectifying channel subfamily J member 11)
PPARGC1A  (PPARG coactivator 1 alpha)


Additional Information