Cell
Volume 118, Issue 3, 6 August 2004, Pages 375-387
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Article
PI3Kγ Modulates the Cardiac Response to Chronic Pressure Overload by Distinct Kinase-Dependent and -Independent Effects

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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 (PI3KγKD/KD) display reduced inflammatory reactions but no alterations in cardiac contractility. We show that, in PI3KγKD/KD hearts, cAMP levels are normal and that PI3Kγ-deficient mice but not PI3KγKD/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.

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These authors contributed equally to this work.