Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice
Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice
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DOI：
10.1128/mcb.22.14.4977-4983.2002
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发表时间：
2002-07-01
影响因子：
5.3
通讯作者：
Kirsch, IR
中科院分区：
文献类型：
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作者：
Cogliati, T;Good, DJ;Kirsch, IR
nhlh 1是一种碱性螺旋-环-螺旋转录因子，其表达仅限于神经系统，并可能在神经元分化中发挥作用。为了直接研究Nhlh 1功能，我们产生了无效小鼠。纯合子突变小鼠易发生过早、成年发作、意外死亡。心电图显示总心率变异性降低、应激诱导的心律失常和压力感受器敏感性受损。这种心律失常的倾向可能是突变小鼠中观察到的死亡的原因。密切相关的转录因子Nhlh 2的杂合性增加了Nhlh 1无效表型的严重程度。在对无效小鼠尸检时，未检测到原发性心脏结构或传导异常的体征。在基础和实验条件下（应激和应激诱导）观察到的心律改变模式表明，副交感神经张力不足可能导致Nhlh 1缺失小鼠的心律失常。Nhlh 1在野生型小鼠发育中的脑干和迷走神经核中的表达进一步支持了这一假设。因此，Nhlh 1突变小鼠可以提供一个模型，以调查自主神经系统的贡献，以mammogenesis。
Nhlh1 is a basic helix-loop-helix transcription factor whose expression is restricted to the nervous system and which may play a role in neuronal differentiation. To directly study Nhlh1 function, we generated null mice. Homozygous mutant mice were predisposed to premature, adult-onset, unexpected death. Electrocardiograms revealed decreased total heart rate variability, stress-induced arrhythmia, and impaired baroreceptor sensitivity. This predisposition to arrhythmia is a likely cause of the observed death in the mutant mice. Heterozygosity for the closely related transcription factor Nhlh2 increased the severity of the Nhlh1-null phenotype. No signs of primary cardiac structural or conduction abnormalities could be detected upon necropsy of the null mice. The pattern of altered heart rhythm observed in basal and experimental conditions (stress and pharmacologically induced) suggests that a deficient parasympathetic tone may contribute to the arrhythmia in the Nhlh1-null mouse. The expression of Nhlh1 in the developing brain stem and in the vagal nuclei in the wild-type mouse further supports this hypothesis. The Nhlh1 mutant mouse may thus provide a model to investigate the contribution of the autonomic nervous system to arrhythmogenesis.