Background— We have recently shown that genetic inactivation of phosphoinositide 3-kinase γ (PI3Kγ), 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 β-adrenergic receptors has been implicated in cardiac hypertrophy and heart failure, suggesting that PI3Kγ might play a role in the pathogenesis of heart disease.

Methods and Results— To determine the role for PI3Kγ in hypertrophy induced by G-protein–coupled receptors and cardiomyopathy, we infused isoproterenol, a β-adrenergic receptor agonist, into PI3Kγ-deficient mice. Compared with controls, isoproterenol infusion in PI3Kγ-deficient mice resulted in an attenuated cardiac hypertrophic response and markedly reduced interstitial fibrosis. Intriguingly, chronic β-adrenergic receptor stimulation triggered impaired heart functions in wild-type mice, whereas PI3Kγ-deficient mice retained their increased heart function and did not develop heart failure. The lack of PI3Kγ attenuated the activation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 signaling pathways in cardiac myocytes in response to isoproterenol. β₁- and β₂-adrenergic receptor densities were decreased by similar amounts in PI3Kγ-deficient and control mice, suggesting that PI3Kγ isoform plays no role in the downregulation of β-adrenergic receptors after chronic β-adrenergic stimulation.

Conclusions— Our data show that PI3Kγ is critical for the induction of hypertrophy, fibrosis, and cardiac dysfunction function in response to β-adrenergic receptor stimulation in vivo. Thus, PI3Kγ may represent a novel therapeutic target for the treatment of decreased cardiac function in heart failure.