Abstract 21531: Inducible Kinase-Independent Effects of Phosphoinositide-3-Kinase Gamma on Cardiac Contractility
Background: Phosphoinositide-3-kinase gamma (PI3Kγ) is a key inflammatory mediator and a fine regulator of cardiac contractility. Interleukin-1β (IL-1β) is a prototypal inflammatory cytokine with demonstrated negative-inotropic effects. We therefore investigated the role of PI3Kγ kinase-dependent and kinase-independent activities in a model of cardiac systolic dysfunction secondary to IL-1β challenge.
Methods: IL-1β (3 μg/kg) was given intraperitoneally in wild-type (WT) mice (C57/B6) as well as in mice with genetic deletion of the gene coding for PI3Kγ(−/−), or with mutation in the kinase activity (kinase-dead) PI3Kγ(KD/KD) which retains all the kinase-independent function of PI3Kγ (N≥4 per group). Echocardiography was performed at baseline and 4 hours after IL-1β to measure left ventricular systolic function.
Results: IL-1β induced a significant reduction in left ventricular fractional shortening in WT (P<0.01), which was associated with a 4-fold increase in cardiac expression of PI3Kγ (P<0.05). The PI3Kγ(−/−) mice were protected from IL-1β induced systolic dysfunction, whereas the PI3Kγ(KD/KD) mice were not, reflecting the lack of involvement of the kinase function (Figure).
Conclusion: Enhanced PI3Kγ expression in the heart modulates cardiac contractility through a kinase-independent mechanism following inflammatory stimulation.
- © 2010 by American Heart Association, Inc.