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

Abstract

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 γ coactivator (PGC)-1α 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-1α in cultured rat neonatal cardiac myocytes in response to hypoxia, indicating that K ATP activity is required to maintain PGC-1α expression under stress conditions. PGC-1α gene deficiency also exacerbated chronic transverse aortic constriction–induced ventricular hypertrophy and dysfunction, suggesting that depletion of PGC-1α 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-1α expression. Furthermore, inhibition of K ATP caused a decrease of FOXO1 associated with PGC-1α promoter. These data indicate that K ATP channels facilitate the cardiac response to stress by regulating PGC-1α and its target genes, at least partially through the FOXO1 pathway.