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.
Department of Genetics, Biology, and Biochemistry, University of Torino, Via Santena 5bis, Italy.
Enrico
E
Patrucco
Antonella
A
Notte
Laura
L
Barberis
Giulio
G
Selvetella
Angelo
A
Maffei
Mara
M
Brancaccio
Stefano
S
Marengo
Giovanni
G
Russo
Ornella
O
Azzolino
Sergei D
SD
Rybalkin
Lorenzo
L
Silengo
Fiorella
F
Altruda
Reinhard
R
Wetzker
Matthias P
MP
Wymann
Giuseppe
G
Lembo
Emilio
E
Hirsch
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006973:Hypertension / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C546764:Pik3cg protein, mouse; C517293:Pde3b protein, mouse