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PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects.

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.

Pubmed ID: 15294162


  • Patrucco E
  • Notte A
  • Barberis L
  • Selvetella G
  • Maffei A
  • Brancaccio M
  • Marengo S
  • Russo G
  • Azzolino O
  • Rybalkin SD
  • Silengo L
  • Altruda F
  • Wetzker R
  • Wymann MP
  • Lembo G
  • Hirsch E



Publication Data

August 6, 2004

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK 21723

Mesh Terms

  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Animals
  • Cell Movement
  • Class Ib Phosphatidylinositol 3-Kinase
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Hypertension
  • Isoenzymes
  • Leukocytes
  • Mice
  • Mitogen-Activated Protein Kinases
  • Myocardium
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction