Cardiac Tissue-Restricted Deletion of Plakoglobin Results in Progressive Cardiomyopathy and Activation of β-Catenin Signaling
Cardiac Tissue-Restricted Deletion of Plakoglobin Results in Progressive Cardiomyopathy and Activation of β-Catenin Signaling
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DOI：
10.1128/mcb.01025-10
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发表时间：
2011-03-01
影响因子：
5.3
通讯作者：
Radice, Glenn L.
中科院分区：
文献类型：
--
作者：
Li, Jifen;Swope, David;Radice, Glenn L.
斑珠蛋白（JUP）基因突变已在致心律失常性右心室心肌病（ARVC）患者中发现。然而，对ARVC发病机制中斑珠蛋白功能障碍的潜在机制仍知之甚少。斑珠蛋白是位于心肌细胞闰盘（ICD）的桥粒和粘附连接的组成部分，在那里它的功能是将钙粘蛋白连接到细胞骨架。此外，斑珠蛋白通过其调节Wnt/β-连环蛋白信号通路的能力作为信号蛋白发挥作用。为了研究斑珠蛋白在ARVC中的作用，我们在小鼠中产生了斑珠蛋白基因的可诱导的心脏限制性敲除（CKO）。斑珠蛋白CKO小鼠表现出与ARVC患者相似的心肌细胞进行性损失、广泛的炎症浸润、纤维组织替代和心功能障碍。ICD桥粒蛋白减少，与斑珠蛋白CKO心脏桥粒超微结构改变一致。尽管间隙连接重塑，斑珠蛋白CKO心脏难治性诱发心律失常。斑珠蛋白的消融引起与激活的AKT和糖原合成酶激酶3 β的抑制相关的β-连环蛋白稳定性增加。最后，β-连环蛋白/TCF转录活性可能有助于斑珠蛋白CKO小鼠的心脏肥大反应。这种ARVC的新模型首次证明了斑珠蛋白如何影响心脏中的β-连环蛋白活性及其对疾病发病机制的影响。
Mutations in the plakoglobin (JUP) gene have been identified in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. However, the mechanisms underlying plakoglobin dysfunction involved in the pathogenesis of ARVC remain poorly understood. Plakoglobin is a component of both desmosomes and adherens junctions located at the intercalated disc (ICD) of cardiomyocytes, where it functions to link cadherins to the cytoskeleton. In addition, plakoglobin functions as a signaling protein via its ability to modulate the Wnt/beta-catenin signaling pathway. To investigate the role of plakoglobin in ARVC, we generated an inducible cardiorestricted knockout (CKO) of the plakoglobin gene in mice. Plakoglobin CKO mice exhibited progressive loss of cardiac myocytes, extensive inflammatory infiltration, fibrous tissue replacement, and cardiac dysfunction similar to those of ARVC patients. Desmosomal proteins from the ICD were decreased, consistent with altered desmosome ultrastructure in plakoglobin CKO hearts. Despite gap junction remodeling, plakoglobin CKO hearts were refractory to induced arrhythmias. Ablation of plakoglobin caused increase beta-catenin stabilization associated with activated AKT and inhibition of glycogen synthase kinase 3 beta. Finally, beta-catenin/TCF transcriptional activity may contribute to the cardiac hypertrophy response in plakoglobin CKO mice. This novel model of ARVC demonstrates for the first time how plakoglobin affects beta-catenin activity in the heart and its implications for disease pathogenesis.