Restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy
Restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy
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DOI：
10.1093/hmg/ddr392
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Shou, Weinian
中科院分区：
文献类型：
--
作者：
Li, Deqiang;Liu, Ying;Shou, Weinian
致心律失常性右室心肌病（ARVC）是一种遗传性心肌病，与心肌纤维脂肪替代和室性心律失常有关。ARVC的一个子集被归类为纳克索斯病，其特征是ARVC和皮肤疾病。在Naxos患者中发现了编码桥粒和粘附连接的主要成分的斑珠蛋白（Jup）基因的纯合功能丧失突变，尽管潜在的机制仍然难以捉摸。我们通过消融心肌细胞中的Jup产生Jup突变小鼠。Jup突变小鼠在很大程度上概括了人类ARVC的临床表现：心室扩张和动脉瘤、心脏纤维化、心脏功能障碍和自发性室性心律失常。超微结构分析显示，桥粒是缺席的Jup突变心肌，而粘附连接和缝隙连接被保存。我们发现室性心律失常与Jup突变心脏的进行性心肌病和纤维化有关。大量细胞死亡导致Jup突变心脏的心肌细胞脱落。尽管在Jup突变心肌细胞中粘附连接处的β-连环蛋白增加，但Wnt/β-连环蛋白介导的信号传导没有改变。在心肌病的早期阶段，发现转化生长因子-β介导的信号在Jup突变的心肌细胞中显著升高，这提示了与ARVC相关的重要致病途径。这些发现为ARVC的发病机制和潜在的治疗干预提供了进一步的见解。
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disorder associated with fibrofatty replacement of myocardium and ventricular arrhythmia. A subset of ARVC is categorized as Naxos disease, which is characterized by ARVC and a cutaneous disorder. A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction, had been identified in Naxos patients, although the underlying mechanism remained elusive. We generated Jup mutant mice by ablating Jup in cardiomyocytes. Jup mutant mice largely recapitulated the clinical manifestation of human ARVC: ventricular dilation and aneurysm, cardiac fibrosis, cardiac dysfunction and spontaneous ventricular arrhythmias. Ultra-structural analyses revealed that desmosomes were absent in Jup mutant myocardia, whereas adherens junctions and gap junctions were preserved. We found that ventricular arrhythmias were associated with progressive cardiomyopathy and fibrosis in Jup mutant hearts. Massive cell death contributed to the cardiomyocyte dropout in Jup mutant hearts. Despite the increase of beta-catenin at adherens junctions in Jup mutant cardiomyoicytes, the Wnt/beta-catenin-mediated signaling was not altered. Transforming growth factor-beta-mediated signaling was found significantly elevated in Jup mutant cardiomyocytes at the early stage of cardiomyopathy, suggesting an important pathogenic pathway for Jup-related ARVC. These findings have provided further insights for the pathogenesis of ARVC and potential therapeutic interventions.