PI3Kγ Modulates the Cardiac Response to Chronic Pressure Overload by Distinct Kinase-Dependent and -Independent Effects

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.

Lipid signalling in disease

“…PI3K has not directly been linked to IgE-allergen-triggered clustering of Fc RI, but the IgE-allergen causes the release of adenosine from mast cells, which signals through GPCRs to activate PI3K ; the resulting peak in PtdIns(3,4,5)P 3 is essential for the in vivo responsiveness of mast cells 103 . In addition, genetic evidence suggests that modulation of PI3K activity could be beneficial in cardiovascular disease 104 , and dual PI3K / inhibitors (for example, TG100-115) have entered clinical trials for myocardial infarction 105 . Owing to the above, PI3K inhibitors have been enthusiastically dubbed the 'aspirin of the twenty-first century' 99 , but single-specificity inhibitors for PI3K and PI3K still await validation for the treatment of human disease.…”

Dual role of proapoptotic BAD in insulin secretion and beta cell survival

“…Other examples of proteins that serve as integral components of multiple signaling pathways include the γ isoform of phosphoinositide-3 kinase, which also binds and regulates phosphodiesterase-3B to modulate both the AKT and cAMP pathways 37 . Glyceraldehyde-3-phosphate dehydrogenase, an abundant glycolytic enzyme, can also interact with the E3-ubiquitin-ligase Siah and translocate to the nucleus to degrade selected proteins, inducing cell death 38 .…”

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

“…Mice lacking PI3Kg (PI3Kg À/À ) or expressing a catalytically inactive PI3Kg mutant (PI3Kg KD/KD ) were generated as previously described [5,43]. Both mutant and control animals derived from 15 generations backcrosses to the C57B6 genetic background.…”