PI3Kγ Modulates the Cardiac Response to Chronic Pressure Overload by Distinct Kinase-Dependent and -Independent Effects

Abstract The G protein-coupled, receptor-activated phosphoinositide 3-kinase γ (PI3Kγ) mediates inflammatory responses and negatively controls cardiac contractility by reducing cAMP concentration. Here, we report that mice carrying a targeted mutation in the PI3Kγ gene causing loss of kinase activity (PI3Kγ KD/KD ) display reduced inflammatory reactions but no alterations in cardiac contractility. We show that, in PI3Kγ KD/KD hearts, cAMP levels are normal and that PI3Kγ-deficient mice but not PI3Kγ KD/KD mice develop dramatic myocardial damage after chronic pressure overload induced by transverse aortic constriction (TAC). Finally, our data indicate that PI3Kγ is an essential component of a complex controlling PDE3B phosphodiesterase-mediated cAMP destruction. Thus, cardiac PI3Kγ participates in two distinct signaling pathways: a kinase-dependent activity that controls PKB/Akt as well as MAPK phosphorylation and contributes to TAC-induced cardiac remodeling, and a kinase-independent activity that relies on protein interactions to regulate PDE3B activity and negatively modulates cardiac contractility.