Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis
Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis
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DOI：
10.1007/s00395-015-0522-5
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发表时间：
2016-01-01
影响因子：
9.5
通讯作者：
Erdmann, Jeanette
中科院分区：
文献类型：
--
作者：
Aherrahrou, Zouhair;Schlossarek, Saskia;Erdmann, Jeanette
心肌病是慢性心力衰竭最常见的原因之一。在肥厚型和扩张型心肌病（DCM）患者中都会发生编码nexilin （NEXN）的基因突变；然而，关于NEXN与这些疾病的病理生理机制和相关性知之甚少。在这里，我们使用组成型NEXN敲除（KO）小鼠模型来评估NEXN的功能作用。杂合子（Het）小鼠杂交产生野生型（WT）、Het和纯合子KO小鼠。出生时，分别有32%、46%和22%的小鼠为WT、Het和KO，这与预期的孟德尔比例接近。出生后第6天，Nexn KO小鼠存活率显著下降，第8天全部死亡。WT和KO小鼠在出生后1、2、4和6天进行表型表征。出生时，WT和KO小鼠的相对心脏重量相似；然而，在第4天，KO组的相对心脏重量比WT组高2.3倍。此外，KO小鼠发展为快速进行性心肌病，左心室扩张和壁变薄，心功能下降。在第6天，KO小鼠出现暴发性DCM表型，其特征是心室扩张和收缩功能障碍。在这一阶段，左心室腔内可见胶原沉积和一些弹性蛋白沉积，类似于心内膜纤维弹性增生症（EFE）的特征。总的来说，这些结果进一步强调了NEXN在DCM中的作用，并提出了在EFE中的新作用。
Cardiomyopathy is one of the most common causes of chronic heart failure worldwide. Mutations in the gene encoding nexilin (NEXN) occur in patients with both hypertrophic and dilated cardiomyopathy (DCM); however, little is known about the pathophysiological mechanisms and relevance of NEXN to these disorders. Here, we evaluated the functional role of NEXN using a constitutive Nexn knock-out (KO) mouse model. Heterozygous (Het) mice were inter-crossed to produce wild-type (WT), Het, and homozygous KO mice. At birth, 32, 46, and 22 % of the mice were WT, Het, and KO, respectively, which is close to the expected Mendelian ratio. After postnatal day 6, the survival of the Nexn KO mice decreased dramatically and all of the animals died by day 8. Phenotypic characterizations of the WT and KO mice were performed at postnatal days 1, 2, 4, and 6. At birth, the relative heart weights of the WT and KO mice were similar; however, at day 4, the relative heart weight of the KO group was 2.3-fold higher than of the WT group. In addition, the KO mice developed rapidly progressive cardiomyopathy with left ventricular dilation and wall thinning and decreased cardiac function. At day 6, the KO mice developed a fulminant DCM phenotype characterized by dilated ventricular chambers and systolic dysfunction. At this stage, collagen deposits and some elastin deposits were observed within the left ventricle cavity, which resembles the features of endomyocardial fibroelastosis (EFE). Overall, these results further emphasize the role of NEXN in DCM and suggest a novel role in EFE.