CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart
CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart
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DOI：
10.1073/pnas.0709118105
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发表时间：
2008-03-18
影响因子：
11.1
通讯作者：
Marban, Eduardo
中科院分区：
文献类型：
--
作者：
Chang, Kuan-Cheng;Barth, Andreas S.;Marban, Eduardo
先天性长或短QT综合征可导致危及生命的室性心动过速和心源性猝死。除了罕见的致病突变外，CAPON（一种神经元型一氧化氮合酶（NOS 1）调节剂）中常见的遗传变异最近在人类全基因组关联研究中与QT间期变异相关。CAPON在心脏复极中的作用从未被怀疑过;事实上，它在心脏中的生理作用（如果有的话）是未知的。为了确定CAPON在心脏中的生物学效应，我们研究了心脏中内源性CAPON蛋白表达和蛋白质-蛋白质相互作用，并在有和没有CAPON过表达的分离的心室肌细胞中进行了电生理学研究。我们发现CAPON蛋白在心脏中表达，并与NOS 1相互作用，通过抑制L-型钙通道加速心脏复极。我们的研究结果为CAPON基因变异与人群中QT间期极值的相关性提供了理论依据。
Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from the rare disease-causing mutations, common genetic variants in CAPON, a neuronal nitric oxide synthase (NOS1) regulator, have recently been associated with QT interval variations in a human whole-genome association study. CAPON had been unsuspected of playing a role in cardiac repolarization; indeed, its physiological role in the heart (if any) is unknown. To define the biological effects of CAPON in the heart, we investigated endogenous CAPON protein expression and protein-protein interactions in the heart and performed electrophysiological studies in isolated ventricular myocytes with and without CAPON overexpression. We find that CAPON protein is expressed in the heart and interacts with NOS1 to accelerate cardiac repolarization by inhibition of L-type calcium channel. Our findings provide a rationale for the association of CAPON gene variants with extremes of the QT interval in human populations.