Cardiac-specific loss of N-cadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis
Cardiac-specific loss of N-cadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis
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DOI：
10.1161/01.res.0000181132.11393.18
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发表时间：
2005-09-02
影响因子：
20.1
通讯作者：
Radice, GL
中科院分区：
文献类型：
--
作者：
Li, JF;Patel, VV;Radice, GL
由大小、分布或功能改变所定义的心室缝隙连接的重塑是病变心肌的一个显著特征。然而，对缝隙连接的组装和维护的调节仍然知之甚少。为了研究N-钙粘蛋白在成人心肌中的功能，我们将N-钙粘附素基因与心脏特异的三苯氧胺诱导的Cre转基因结合使用。突变的动物看起来很活跃和健康，直到它们从心脏中删除N-钙粘素后大约两个月突然死亡。电生理分析显示，突变动物的脑室传导异常，包括QRS波幅减小，与心肌电耦合丧失一致。在N-钙粘附素缺失的心肌细胞中观察到缝隙连接蛋白Cx43和Cx40的表达显著减少。光学标测结果显示，缝隙连接蛋白功能紊乱导致心室传导速度减慢。我们的数据表明，心脏病中N-钙粘附素/连环蛋白复合体的扰动可能是一个潜在的原因，通过破坏细胞表面缝隙连接的稳定而导致致心律失常底物的建立。
The remodeling of ventricular gap junctions, as defined by changes in size, distribution, or function, is a prominent feature of diseased myocardium. However, the regulation of assembly and maintenance of gap junctions remains poorly understood. To investigate N-cadherin function in the adult myocardium, we used a floxed N-cadherin gene in conjunction with a cardiac-specific tamoxifen-inducible Cre transgene. The mutant animals appeared active and healthy until their sudden death approximate to 2 months after deleting N-cadherin from the heart. Electrophysiologic analysis revealed abnormal conduction in the ventricles of mutant animals, including diminished QRS complex amplitude consistent with loss of electrical coupling in the myocardium. A significant decrease in the gap junction proteins, connexin-43 and connexin-40, was observed in N-cadherin-depleted myocytes. Perturbation of connexin function resulted in decreased ventricular conduction velocity, as determined by optical mapping. Our data suggest that perturbation of the N-cadherin/catenin complex in heart disease may be an underlying cause, leading to the establishment of the arrythmogenic substrate by destabilizing gap junctions at the cell surface.