The G protein-coupled, receptor-activated phosphoinositide 3-kinase gamma (PI3Kgamma) mediates inflammatory responses and negatively controls cardiac contractility by reducing cAMP concentration. Here, we report that mice carrying a targeted mutation in the PI3Kgamma gene causing loss of kinase activity (PI3K-gamma(KD/KD)) display reduced inflammatory reactions but no alterations in cardiac contractility. We show that, in PI3K-gamma(KD/KD) hearts, cAMP levels are normal and that PI3Kgamma-deficient mice but not PI3Kgamma(KD/KD) mice develop dramatic myocardial damage after chronic pressure overload induced by transverse aortic constriction (TAC). Finally, our data indicate that PI3Kgamma is an essential component of a complex controlling PDE3B phosphodiesterase-mediated cAMP destruction. Thus, cardiac PI3Kgamma 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.
PI3Kgamma Modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and independent effects / Patrucco, E.; Notte, A.; Barberis, L.; Selvetella, G.; Maffei, A.; Brancaccio, M.; Marengo, S.; Russo, G.; Azzolino, O.; Silengo, L.; Altruda, F.; Wetzker, R.; Wymann, M.; Lembo, Giuseppe; Hirsch, E.. - In: CELL. - ISSN 0092-8674. - STAMPA. - 118:3(2004), pp. 375-387. [10.1016/j.cell.2004.07.017]
PI3Kgamma Modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and independent effects.
LEMBO, Giuseppe;
2004
Abstract
The G protein-coupled, receptor-activated phosphoinositide 3-kinase gamma (PI3Kgamma) mediates inflammatory responses and negatively controls cardiac contractility by reducing cAMP concentration. Here, we report that mice carrying a targeted mutation in the PI3Kgamma gene causing loss of kinase activity (PI3K-gamma(KD/KD)) display reduced inflammatory reactions but no alterations in cardiac contractility. We show that, in PI3K-gamma(KD/KD) hearts, cAMP levels are normal and that PI3Kgamma-deficient mice but not PI3Kgamma(KD/KD) mice develop dramatic myocardial damage after chronic pressure overload induced by transverse aortic constriction (TAC). Finally, our data indicate that PI3Kgamma is an essential component of a complex controlling PDE3B phosphodiesterase-mediated cAMP destruction. Thus, cardiac PI3Kgamma 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
