Desmosomes: emerging pathways and non-canonical functions in cardiac arrhythmias and disease.
Desmosomes: emerging pathways and non-canonical functions in cardiac arrhythmias and disease.
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DOI：
10.1007/s12551-021-00829-2
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发表时间：
2021-10
影响因子：
--
通讯作者：
Sheikh F
中科院分区：
文献类型：
--
作者：
Zhang J;Liang Y;Bradford WH;Sheikh F
桥粒是心肌细胞中重要的黏附结构，其突变/缺失与遗传性心脏病——心律失常性右室心肌病（ARVC）有关。早期研究表明，桥粒体蛋白丢失可引发ARVC疾病特征，包括结构重塑、心律失常和炎症；然而，导致各种疾病表现的确切机制尚不完全清楚。最近的机制研究表明，蛋白质降解组分CSN6是一种常驻的心脏桥粒蛋白，它选择性地限制心肌细胞桥粒降解和疾病。这表明蛋白质降解缺陷可引发ARVC的结构重塑。此外，arvc相关突变的一个子集对calpain介导的降解表现出增强的易感性，进一步支持了这些机制在疾病中的相关性。在ARVC患者和模型系统中，桥粒体基因突变/丢失已被证明在没有结构性疾病的情况下影响心律失常途径。研究表明，连接蛋白、钙处理机制和钠通道是心律失常的早期驱动因素，这表明这些可能是桥粒调节电功能的不同途径。新出现的证据表明炎症可能是疾病发病的早期机制，因为临床报告显示心肌炎和ARVC之间存在重叠。最近的研究集中在桥胞体突变/丢失与炎症过程（包括自身抗体和信号通路）之间的关系，以了解炎症在ARVC发病机制中的作用。一个特别的重点将是剖析正在进行的研究领域，以突出与桥粒体突变/丢失相关的各种致病途径。
Desmosomes are critical adhesion structures in cardiomyocytes, with mutation/loss linked to the heritable cardiac disease, arrhythmogenic right ventricular cardiomyopathy (ARVC). Early studies revealed the ability of desmosomal protein loss to trigger ARVC disease features including structural remodeling, arrhythmias, and inflammation; however, the precise mechanisms contributing to diverse disease presentations are not fully understood. Recent mechanistic studies demonstrated the protein degradation component CSN6 is a resident cardiac desmosomal protein which selectively restricts cardiomyocyte desmosomal degradation and disease. This suggests defects in protein degradation can trigger the structural remodeling underlying ARVC. Additionally, a subset of ARVC-related mutations show enhanced vulnerability to calpain-mediated degradation, further supporting the relevance of these mechanisms in disease. Desmosomal gene mutations/loss has been shown to impact arrhythmogenic pathways in the absence of structural disease within ARVC patients and model systems. Studies have shown the involvement of connexins, calcium handling machinery, and sodium channels as early drivers of arrhythmias, suggesting these may be distinct pathways regulating electrical function from the desmosome. Emerging evidence has suggested inflammation may be an early mechanism in disease pathogenesis, as clinical reports have shown an overlap between myocarditis and ARVC. Recent studies focus on the association between desmosomal mutations/loss and inflammatory processes including autoantibodies and signaling pathways as a way to understand the involvement of inflammation in ARVC pathogenesis. A specific focus will be to dissect ongoing fields of investigation to highlight diverse pathogenic pathways associated with desmosomal mutations/loss.
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影响因子：
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