Loss of cadherin-binding proteins beta-catenin and plakoglobin in the heart leads to gap junction remodeling and arrhythmogenesis.
Loss of cadherin-binding proteins beta-catenin and plakoglobin in the heart leads to gap junction remodeling and arrhythmogenesis.
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DOI：
10.1128/mcb.06188-11
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发表时间：
2012-03-01
影响因子：
5.3
通讯作者：
Radice, Glenn L
中科院分区：
文献类型：
--
作者：
Swope, David;Cheng, Lan;Radice, Glenn L
心律失常性右心室心肌病（ARVC）是一种遗传性心肌疾病，可导致年轻人心源性猝死（SCD）。几乎一半的ARVC患者在编码桥粒细胞粘附蛋白的基因中存在突变，包括斑珠蛋白（JUP）。我们先前报道了心脏组织特异性斑珠蛋白（PG）基因敲除（PG CKO）小鼠没有明显的传导异常，存活时间比预期的长。重要的是，PG同系物β-连环蛋白（CTNNB 1）与PG CKO心脏中的差距连接蛋白连接蛋白43（Cx43）的相关性增加。为了确定在没有PG的情况下是否需要β-连环蛋白来维持心脏传导，我们产生了心脏中专门缺乏PG和β-连环蛋白的小鼠（即，双敲除[DKO]）。DKO小鼠表现出心肌病、纤维组织替代和导致SCD的传导异常。钙粘蛋白连接蛋白的丢失导致椎间盘（ICD）结构的溶解。此外，含Cx43的间隙连接斑块在ICD处减少，这与DKO心脏的致血栓性一致。最后，动态心电图监测捕捉到DKO小鼠自发性致死性室性心律失常的突然发作。总之，这些研究表明，N-钙粘蛋白结合的合作伙伴，PG和β-连环蛋白，是必不可少的维持机械电耦合在心脏。
Arrhythmic right ventricular cardiomyopathy (ARVC) is a hereditary heart muscle disease that causes sudden cardiac death (SCD) in young people. Almost half of ARVC patients have a mutation in genes encoding cell adhesion proteins of the desmosome, including plakoglobin (JUP). We previously reported that cardiac tissue-specific plakoglobin (PG) knockout (PG CKO) mice have no apparent conduction abnormality and survive longer than expected. Importantly, the PG homolog, beta-catenin (CTNNB1), showed increased association with the gap junction protein connexin43 (Cx43) in PG CKO hearts. To determine whether beta-catenin is required to maintain cardiac conduction in the absence of PG, we generated mice lacking both PG and beta-catenin specifically in the heart (i.e., double knockout [DKO]). The DKO mice exhibited cardiomyopathy, fibrous tissue replacement, and conduction abnormalities resulting in SCD. Loss of the cadherin linker proteins resulted in dissolution of the intercalated disc (ICD) structure. Moreover, Cx43-containing gap junction plaques were reduced at the ICD, consistent with the arrhythmogenicity of the DKO hearts. Finally, ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous lethal ventricular arrhythmia in the DKO mice. In conclusion, these studies demonstrate that the N-cadherin-binding partners, PG and beta-catenin, are indispensable for maintaining mechanoelectrical coupling in the heart.