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

Area of Science:

• Cardiovascular Biology
• Molecular Signaling
• Inflammation Research

Background:

• Phosphoinositide 3-kinase gamma (PI3Kgamma) is a G protein-coupled receptor-activated enzyme.
• PI3Kgamma is known to mediate inflammatory responses and negatively regulate cardiac contractility by reducing cyclic adenosine monophosphate (cAMP) levels.

Purpose of the Study:

• To investigate the distinct roles of PI3Kgamma's kinase activity and its kinase-independent functions in cardiac physiology and pathology.
• To elucidate the mechanisms by which PI3Kgamma influences cardiac contractility and response to pressure overload.

Main Methods:

• Utilized mice with a targeted mutation in the PI3Kgamma gene leading to loss of kinase activity (PI3KgammaKD/KD).
• Assessed inflammatory reactions, cardiac contractility, and cAMP levels in PI3KgammaKD/KD and PI3Kgamma-deficient mice.
• Induced chronic pressure overload using transverse aortic constriction (TAC) to evaluate myocardial damage.

Main Results:

• PI3KgammaKD/KD mice exhibited reduced inflammatory responses but maintained normal cardiac contractility and cAMP levels.
• PI3Kgamma-deficient mice, unlike PI3KgammaKD/KD mice, developed significant myocardial damage after TAC.
• PI3Kgamma was identified as a crucial component of a complex regulating phosphodiesterase 3B (PDE3B)-mediated cAMP degradation.

Conclusions:

• Cardiac PI3Kgamma possesses both kinase-dependent and kinase-independent activities.
• Kinase-dependent PI3Kgamma activity influences PKB/Akt and MAPK phosphorylation, contributing to cardiac remodeling post-TAC.
• Kinase-independent PI3Kgamma activity regulates PDE3B, thereby modulating cardiac contractility.