Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish
Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish
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DOI：
10.1073/pnas.0502679102
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发表时间：
2005-12-06
影响因子：
11.1
通讯作者：
Chen, JN
中科院分区：
文献类型：
--
作者：
Langenbacher, AD;Dong, Y;Chen, JN
心脏颤动是心律失常的一种形式，是栓塞性中风和心力衰竭相关死亡的最常见原因。心脏颤动的分子机制在很大程度上是未知的。在这里，我们报告了一个斑马鱼心脏颤动模型。斑马鱼震颤（震颤）突变体的心脏表现出混乱的运动，不能发展同步收缩。钙成像显示，在3个心肌细胞中没有正常的钙瞬变，3突变的分子克隆显示，3位点编码斑马鱼心脏特异性钠钙交换器（NCX） 1, ncx1。在三个突变胚胎中，ncx1或其他钙处理分子的强制表达以剂量依赖的方式恢复了同步心跳，证明了钙稳态在维持胚胎心功能中的关键作用。通过创建斑马鱼嵌合胚胎，我们发现散发性NCX1h-null细胞不足以破坏正常的心脏功能，但在三个突变心脏中聚集的野生型心肌细胞一致收缩。这些数据表明钙稳态和ncx1在建立斑马鱼胚胎心脏节律性收缩中的重要作用。
Cardiac fibrillation, a form of cardiac arrhythmia, is the most common cause of embolic stroke and death associated with heart failure. The molecular mechanisms underlying cardiac fibrillation are largely unknown. Here we report a zebrafish model for cardiac fibrillation. The hearts of zebrafish tremblor (tre) mutants exhibit chaotic movements and fail to develop synchronized contractions. Calcium imaging showed that normal calcium transients are absent in tre cardiomyocytes, and molecular cloning of the tre mutation revealed that the tre locus encodes the zebrafish cardiac-specific sodium-calcium exchanger (NCX) 1, NCX1h. Forced expression of NCX1h or other calcium-handling molecules restored synchronized heartbeats in tre mutant embryos in a dosage-dependent manner, demonstrating the critical role of calcium homeostasis in maintaining embryonic cardiac function. By creating mosaic zebrafish embryos, we showed that sporadic NCX1h-null cells were not sufficient to disrupt normal cardiac function, but clustered wild-type cardiomyocytes contract in unison in tre mutant hearts. These data signify the essential role of calcium homeostasis and NCX1h in establishing rhythmic contraction in the embryonic zebrafish heart.