Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias
Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias
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DOI：
10.1161/circep.116.003923
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发表时间：
2016-12-01
影响因子：
8.4
通讯作者：
Isom, Lori L.
中科院分区：
文献类型：
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作者：
Bao, Yangyang;Willis, B. Cicero;Isom, Lori L.
背景-编码电压门控钠通道β 2亚单位的SCN 2B突变与人类心律失常有关，包括心房颤动和Brugada综合征。正因为如此，我们建议，β 2-亚基发挥关键作用，在建立或维持正常的心脏电activityinvivo.Methods和结果，以了解β 2在心脏的病理生理作用，我们调查了Scn 2b空小鼠的心脏表型。我们观察到心室肌细胞的钠和钾电流密度降低，以及右心室流出道区域的传导减慢。功能性折返，由减慢的传导，延长复极，和室性早搏的发病率增加之间的相互作用，被认为是自发性多形性室性心动过速的机制。Scn 5a转录水平在Scn 2b空和野生型心室中相似，Na-v 1.5蛋白的水平也相似，这表明与以前在神经元中的工作相似，心室中β 2亚基的主要功能是陪伴电压门控钠通道α亚基进入质膜。有趣的是，Scn 2b缺失导致心脏中的区域特异性效应。与野生型相比，scn 2b无效心房具有正常水平的钠电流密度。Scn 2b空心脏更容易受到心房颤动，增加了纤维化水平，和更高的复极离散度比野生型littermates. Conclusions基因缺失的Scn 2b在小鼠的结果在室性和房性心律失常，与报告的SCN 2B突变在人类患者一致。
Background-Mutations in SCN2B, encoding voltage-gated sodium channel beta 2-subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that beta 2-subunits play critical roles in the establishment or maintenance of normal cardiac electric activity in vivo.Methods and Results-To understand the pathophysiological roles of beta 2 in the heart, we investigated the cardiac phenotype of Scn2b null mice. We observed reduced sodium and potassium current densities in ventricular myocytes, as well as conduction slowing in the right ventricular outflow tract region. Functional reentry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes, was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. Scn5a transcript levels were similar in Scn2b null and wild-type ventricles, as were levels of Na-v 1.5 protein, suggesting that similar to the previous work in neurons, the major function of beta 2-subunits in the ventricle is to chaperone voltage-gated sodium channel alpha-subunits to the plasma membrane. Interestingly, Scn2b deletion resulted in region-specific effects in the heart. Scn2b null atria had normal levels of sodium current density compared with wild type. Scn2b null hearts were more susceptible to atrial fibrillation, had increased levels of fibrosis, and higher repolarization dispersion than wild-type littermates.Conclusions-Genetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias, consistent with reported SCN2B mutations in human patients.