Loss of PI3Kγ in mice led to premature ventricular contractions and sustained ventricular tachycardia upon adrenergic stimulation due to abnormal cAMP accumulation and hyperphosphorylation.
PI3Kγ acts as a scaffold to coordinate PDE3 and PDE4 isoforms, preventing abnormal cAMP accumulation and calcium-dependent ventricular arrhythmias during adrenergic stimulation.
BACKGROUND: Phosphoinositide 3-kinase γ (PI3Kγ) signaling engaged by β-adrenergic receptors is pivotal in the regulation of myocardial contractility and remodeling. However, the role of PI3Kγ in catecholamine-induced arrhythmia is currently unknown. METHODS AND RESULTS: Mice lacking PI3Kγ (PI3Kγ(-/-)) showed runs of premature ventricular contractions on adrenergic stimulation that could be rescued by a selective β(2)-adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after β(2)-adrenergic receptor activation in PI3Kγ(-/-) cardiomyocytes that depended on the loss of the scaffold but not of the catalytic activity of PI3Kγ. Downstream from β-adrenergic receptors, PI3Kγ was found to participate in multiprotein complexes linking protein kinase A to the activation of phosphodiesterase (PDE) 3A, PDE4A, and PDE4B but not of PDE4D. These PI3Kγ-regulated PDEs lowered cAMP and limited protein kinase A-mediated phosphorylation of L-type calcium channel (Ca(v)1.2) and phospholamban. In PI3Kγ(-/-) cardiomyocytes, Ca(v)1.2 and phospholamban were hyperphosphorylated, leading to increased Ca(2+) spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3Kγ(-/-) cardiomyocytes showed spontaneous Ca(2+) release events and developed arrhythmic calcium transients. CONCLUSIONS: PI3Kγ coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia.
Ghigo et al. (Tue,) conducted a other in Catecholamine-induced ventricular arrhythmia. PI3Kγ knockout was evaluated on Ventricular arrhythmia and cAMP accumulation. Loss of PI3Kγ in mice led to premature ventricular contractions and sustained ventricular tachycardia upon adrenergic stimulation due to abnormal cAMP accumulation and hyperphosphorylation.