Abstract 272: Disruption Of Cardiac Specific Sarcolemmal Atp Sensitive Potassium Channel (skAtp) Activity Diminishes Cardiac Stress Handling Capacity By Impairing Pgc-1alpha Dependent Mitochondrial Biogenesis
sKATP channels act as metabolic sensors that are critical for adaptation of the left ventricle (LV) to stress. This study examined the mechanism by which sKATP dysfunction impairs the LV response to stress using a transgenic mouse strain with cardiac specific disruption of sKATP (Tg mice). Although there were no significant differences in LV mass or function between the Tg mice and their wild type littermates (Wt) under unstressed conditions, the Tg mice demonstrated a markedly abnormal response to pressure overload produced by transverse aortic constriction (TAC). Thus, after TAC of 4 weeks duration, Tg mice developed more severe LV dilation with LV ejection fraction decreasing to 49.9±5% vs. 72±5% in Wt (p<0.05), and more severe pulmonary congestion (2.9-fold increase of lung weight) as compared to WT (1.4-fold increase of lung weight; p<0.05). Tg mice had significantly decreased expression of a group genes related to myocardial fatty acid oxidation and mitochondrial respiration at both protein and mRNA levels (such as cytochrome C, COXIII, UCP3, CPT-1b) after TAC, and this was associated with decreased protein and mRNA levels of PGC-1α, a master regulator of mitochondrial biogenesis. Furthermore, the KATP blocker glibenclamide (glib) or selective knockdown of the SUR2A subunit of KATP repressed the expression of PGC-1α and the luciferase reporter activity driven by the PGC-1α promoter in cultured cardiac myocytes in response to hypoxia, indicating that KATP activity is required to maintain the expression of PGC-1α and its downstream target genes under stress conditions. Previous studies showed that p-Akt can repress PGC-1α expression by regulating FOXO1 degradation. We found that Tg mice had increased p-Akt and decreased FOXO1 after TAC. In addition, inhibition of KATP by glib or knockdown of SUR2A caused an increase of p-Akt and a decrease in the nuclear fraction of FOXO1 in myocytes. ChIP assay showed that FOXO1 association with the PGC-1α promoter was decreased when channel activity was blocked with glib or knockdown of SUR2A, indicating that disruption of KATP resulted in decreases of FOXO1 activity and PGC-1α expression. These data indicate that KATP channels facilitate the cardiac response to stress by regulating PGC-1α and its target genes.