A63. Selective activation of PI3Kα contributes to left ventricular hypertrophy during cardiac recovery from heart failure

Activation of phosphoinositide-3 kinase (PI3K) is essential for basal cell growth, relating to adaptive (physiologic) and maladaptive (pathologic) cardiac hypertrophy, however the roles of the distinct PI3K isoforms in heart failure remain unclear. This study was to investigate PI3Kα and PI3Kγ in cardiac hypertrophy and remodeling during the development of heart failure and cardiac recovery from CHF. Dogs were chronically instrumented for measurement of left ventricular (LV) pressure and dimension. Heart failure (CHF) was induced by rapid right ventricular pacing (250 bpm) for 3–4 weeks, in which LV contractile function was depressed and myocardial gene expression of ANP and CK-B were increased. Cardiac recovery (CR) was allowed by the termination of cardiac pacing for 5 weeks after CHF, with 80–90% restoration of LV contractile function and normalization of myocardial ANF and CK-B gene expression. Importantly, cardiac compensatory hypertrophy was developed during CR with 25% increase in LV weight, We found that the expression of PI3Kγ increased by 4-fold in CHF and returned to the control level in CR. In contrast, the expression PI3Kα in CHF was not different from control, but significantly increased by 3-fold in CR, accompanied an increase in the phosphorylation of Akt, GSK3β, β-catenin, mTOR and P70S6K. Thus, our results suggest that the selective activation of PI3Kα, through Akt, GSK-3β and mTOR signaling pathways, may contribute to the development of cardiac compensatory hypertrophy and functional restoration during cardiac recovery from CHF. In contrast, the activation of PI3Kγ may be associated with the development of CHF, which can be reversed during recovery.