Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways
Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways
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DOI：
10.1172/jci44470
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发表时间：
2011-02-01
影响因子：
15.9
通讯作者：
Epstein, Jonathan A.
中科院分区：
文献类型：
--
作者：
Rentschler, Stacey;Harris, Brett S.;Epstein, Jonathan A.
心室预激是预白色综合征的特征，是由于存在旁路引起的，旁路可以快速地将电脉冲从心房传导到心室，而没有房室结（AV）固有的延迟特性。预激与快速性心律失常、心悸、晕厥和猝死的风险增加相关。虽然预激综合征的病理学和电生理学特征很好，发育机制知之甚少，很少有动物模型，忠实地概括了人类疾病的描述。在这里，我们表明，激活Notch信号在发育中的小鼠心肌可以产生完全渗透性旁路和心室预激。相反，发育中心肌中Notch信号的抑制导致AV结发育不全，表达连接蛋白-30.2（Cx30.2）的慢传导细胞特异性丧失，并导致生理AV传导延迟的丧失。总之，我们的研究结果表明，Notch调节房室管胚胎心肌功能成熟的专门的传导系统的发展过程中。我们的研究结果还表明，心室预激可以产生不适当的图案的AV管衍生的心肌。
Ventricular preexcitation, which characterizes Wolff-Parkinson-White syndrome, is caused by the presence of accessory pathways that can rapidly conduct electrical impulses from atria to ventricles, without the intrinsic delay characteristic of the atrioventricular (AV) node. Preexcitation is associated with an increased risk of tachyarrhythmia, palpitations, syncope, and sudden death. Although the pathology and electrophysiology of preexcitation syndromes are well characterized, the developmental mechanisms are poorly understood, and few animal models that faithfully recapitulate the human disorder have been described. Here we show that activation of Notch signaling in the developing myocardium of mice can produce fully penetrant accessory pathways and ventricular preexcitation. Conversely, inhibition of Notch signaling in the developing myocardium resulted in a hypoplastic AV node, with specific loss of slow-conducting cells expressing connexin-30.2 (Cx30.2) and a resulting loss of physiologic AV conduction delay. Taken together, our results suggest that Notch regulates the functional maturation of AV canal embryonic myocardium during the development of the specialized conduction system. Our results also show that ventricular preexcitation can arise from inappropriate patterning of the AV canal-derived myocardium.