PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects |
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Authors: | Patrucco Enrico Notte Antonella Barberis Laura Selvetella Giulio Maffei Angelo Brancaccio Mara Marengo Stefano Russo Giovanni Azzolino Ornella Rybalkin Sergei D Silengo Lorenzo Altruda Fiorella Wetzker Reinhard Wymann Matthias P Lembo Giuseppe Hirsch Emilio |
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Affiliation: | Department of Genetics, Biology, and Biochemistry, University of Torino, Via Santena 5bis, Italy. |
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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 (PI3KgammaKD/KD) display reduced inflammatory reactions but no alterations in cardiac contractility. We show that, in PI3KgammaKD/KD hearts, cAMP levels are normal and that PI3Kgamma-deficient mice but not PI3KgammaKD/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. |
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