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

Enrico Patrucco, Antonella Notte, Laura Barberis, Giulio Selvetella, Angelo Maffei, Mara Brancaccio, Stefano Marengo, Giovanni Russo, Ornella Azzolino, Sergei D. Rybalkin, Lorenzo Silengo, Fiorella Altruda, Reinhard Wetzker, Matthias P. Wymann, Giuseppe Lembo, Emilio Hirsch

Research output: Contribution to journalArticlepeer-review


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 PI3Kγ KD/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.

Original languageEnglish
Pages (from-to)375-387
Number of pages13
Issue number3
Publication statusPublished - Aug 6 2004

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology


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