Phosphoinositide 3-Kinase gamma Protects Against Catecholamine-Induced Ventricular Arrhythmia Through Protein Kinase A-Mediated Regulation of Distinct Phosphodiesterases | |
Article | |
关键词: CAMP-SPECIFIC PHOSPHODIESTERASE; BETA(2)-ADRENERGIC STIMULATION; SIGNALING COMPLEXES; HEART-FAILURE; PI3K-GAMMA; ISOFORMS; PDE3; PHOSPHORYLATION; MICRODOMAINS; ASSOCIATION; | |
DOI : 10.1161/CIRCULATIONAHA.112.114074 | |
来源: SCIE |
【 摘 要 】
Background-Phosphoinositide 3-kinase gamma (PI3K gamma) signaling engaged by beta-adrenergic receptors is pivotal in the regulation of myocardial contractility and remodeling. However, the role of PI3K gamma in catecholamine-induced arrhythmia is currently unknown. Methods and Results-Mice lacking PI3K gamma (PI3K gamma(-/-)) showed runs of premature ventricular contractions on adrenergic stimulation that could be rescued by a selective beta(2)-adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after beta(2)-adrenergic receptor activation in PI3K (/) cardiomyocytes that depended on the loss of the scaffold but not of the catalytic activity of PI3K gamma. Downstream from beta-adrenergic receptors, PI3K gamma 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 PI3K gamma-regulated PDEs lowered cAMP and limited protein kinase A-mediated phosphorylation of L-type calcium channel (Ca(v)1.2) and phospholamban. In PI3K gamma(-/-) cardiomyocytes, Ca(v)1.2 and phospholamban were hyperphosphorylated, leading to increased Ca2+ spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3K gamma(-/-) cardiomyocytes showed spontaneous Ca2+ release events and developed arrhythmic calcium transients. Conclusions-PI3K gamma coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia. (Circulation. 2012;126:2073-2083.)
【 授权许可】
Free