Phosphoinositide 3-Kinase –Deficient Mice Are Protected From Isoproterenol-Induced Heart Failure

Background—We have recently shown that genetic inactivation of phosphoinositide 3-kinase (PI3K ), the isoform linked to G-protein–coupled receptors, results in increased cardiac contractility with no effect on basal cell size. Signaling via the G-protein–coupled -adrenergic receptors has been implicated in cardiac hypertrophy and heart failure, suggesting that PI3K might play a role in the pathogenesis of heart disease. Methods and Results—To determine the role for PI3K in hypertrophy induced by G-protein–coupled receptors and cardiomyopathy, we infused isoproterenol, a -adrenergic receptor agonist, into PI3K -deficient mice. Compared with controls, isoproterenol infusion in PI3K -deficient mice resulted in an attenuated cardiac hypertrophic response and markedly reduced interstitial fibrosis. Intriguingly, chronic -adrenergic receptor stimulation triggered impaired heart functions in wild-type mice, whereas PI3K -deficient mice retained their increased heart function and did not develop heart failure. The lack of PI3K attenuated the activation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 signaling pathways in cardiac myocytes in response to isoproterenol. 1and 2-adrenergic receptor densities were decreased by similar amounts in PI3K -deficient and control mice, suggesting that PI3K isoform plays no role in the downregulation of -adrenergic receptors after chronic -adrenergic stimulation. Conclusions—Our data show that PI3K is critical for the induction of hypertrophy, fibrosis, and cardiac dysfunction function in response to -adrenergic receptor stimulation in vivo. Thus, PI3K may represent a novel therapeutic target for the treatment of decreased cardiac function in heart failure. (Circulation. 2003;108:2147-2152.)