[HTML][HTML] PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and-independent effects

E Patrucco, A Notte, L Barberis, G Selvetella, A Maffei… - Cell, 2004 - cell.com
E Patrucco, A Notte, L Barberis, G Selvetella, A Maffei, M Brancaccio, S Marengo, G Russo…
Cell, 2004cell.com
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 …
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.
cell.com