Abstract 11982: Constitutive Activation of PI3K Does Not Prevent Mitochondrial or Contractile Dysfunction in Pressure Overload Cardiac Hypertrophy
Class 1A phosphatidylinositol 3-kinase (PI3K) signaling is required for increasing mitochondrial fatty acid oxidation (FAO) capacity in response to physiological cardiac hypertrophy (O'Neill et al Cell Metabolism, 2007). To determine if PI3K signaling may modulate mitochondrial function in pathological cardiac hypertrophy, we examined mitochondrial and contractile function in the hearts of mice with transgenic overexpression of a constitutively active (caPI3K) or dominant negative (dnPI3K) PI3K transgene following transverse aortic constriction (TAC). Heart weights post-TAC were similar in WT, caPI3K and dnPI3K mice, but the fold increase (sham vs. WT) of 44.1 ± 9.7 vs. 31.2 ± 5.6 vs. 81.9 ± 23.5 % of baseline respectively, (P<0.05) were different because of baseline differences in heart size. PI3K activation as measured by Akt/PKB phosphorylation at Ser 473 and Thr308 were increased by 2.0 and 5.5 fold respectively in caPI3K mice (P<0.05) and decreased by 0.7 and 0.8 fold in dnPI3K mice compared to WT mice post-TAC. Hypertrophy markers BNP, ANP and ACTA1 were induced in mice of all genotypes post-TAC. Post-TAC there were no differences in fractional shortening and + dP/dt were equivalently reduced in all genotypes. At baseline, maximal ADP-stimulated mitochondrial oxygen consumption (VADP, WT vs. caPI3K vs. dnPI3K: 13.6 ± 0.5 vs. 15.9 ± 0.9 vs. 13.7 ± 0.6 nmolO2/min/mgdw, P<0.05) and ATP synthesis (31.2 ± 3.9 vs. 36.3 ± 3.6 vs. 26.8 ± 4.7 nmol/min/mgdw, P<0.05) using palmitoyl carnitine as a substrate were higher in hearts from caPI3K mice, but VADP (11.0 ± 0.4 vs. 12.3 ± 0.5 vs. 11.9 ± 0.5) and ATP synthesis (28.6 ± 2.4 vs. 26.9 ± 2.7 vs. 25.0 ± 1.7) were significantly and equivalently decreased in mice of all genotypes by TAC. Expression of FAO and OXPHOS genes were unchanged in sham caPI3K hearts, but were reduced in sham dnPI3K hearts. Following TAC, the expression levels of these genes were equivalently reduced in WT and caPI3K hearts and were further reduced by banding in dnPI3K hearts. Thus, whereas PI3K activity modulates mitochondrial function in unstressed hearts and in response to physiological hypertrophy, PI3K signaling is dispensable with regards to the mitochondrial adaptations to pressure overload cardiac hypertrophy.
- © 2011 by American Heart Association, Inc.