The intercalated disk (ID), a highly organized adhesion structure connecting neighboring cardiomyocytes, fulfills mechanical and electrical signaling communication to ensure normal heart function. Lipoprotein receptor-related protein 6 (LRP6) is a co-receptor inducing canonical Wnt/β-catenin signaling. It was recently reported that LRP6 deficiency in cardiomyocytes predisposes to arrhythmia independent of Wnt signaling. However, whether LRP6 directly regulates the structure of IDs requires further investigation. The aim of the present study was to explore the role of LRP6 in IDs and the potential underlying mechanisms by inducible cardiac-specific LRP6 knockout mice. The results revealed that LRP6 was predominately expressed in the cell membrane, including the IDs of cardiomyocytes. Tamoxifen-inducible cardiac-specific LRP6 knockout mice displayed overt cardiac dysfunction and disruption of ID structure. Further analysis revealed that cardiac LRP6 deficiency induced the imbalance of ID component proteins, characterized by the sharply decreased expression of connexin 43 (Cx43) and the significantly increased expression of N-cadherin, desmoplakin and γ-catenin in tissue lysates or membrane fraction from the left ventricle. STRING database analysis indicated that β-catenin, but no other ID-associated proteins, interacted with LRP6. Our immunoprecipitation analysis demonstrated that LRP6 strongly interacted with Cx43, N-cadherin and γ-catenin, and weakly interacted with β-catenin, whereas there was no association with desmoplakin. In response to LRP6 deficiency, the recruitment of β- or γ-catenin to N-cadherin was increased, but they displayed little interaction with Cx43. In conclusion, LRP6 is required to maintain the integrity of ID structure and the balance of ID proteins, and the interaction between LRP6 and Cx43, N-cadherin and γ-catenin may be involved in this process.

中文翻译：

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需要脂蛋白受体相关蛋白6来保持插入的盘完整性。

插层盘（ID）是连接相邻心肌细胞的高度组织化的粘附结构，可实现机械和电信号传递，以确保正常的心脏功能。脂蛋白受体相关蛋白6（LRP6）是诱导经典Wnt /β-catenin信号转导的共受体。最近有报道说，心肌细胞中LRP6的缺乏会导致心律失常，而与Wnt信号无关。但是，LRP6是否直接调节ID的结构还需要进一步研究。本研究的目的是探讨LRP6在ID中的作用以及潜在的诱导性心脏特异性LRP6基因敲除小鼠的潜在机制。结果表明，LRP6主要在细胞膜中表达，包括心肌细胞的ID。他莫昔芬诱导的心脏特异性LRP6基因敲除小鼠表现出明显的心脏功能障碍和ID结构破坏。进一步的分析显示，心脏LRP6缺乏会引起ID成分蛋白的失衡，其特征在于连接蛋白43（Cx43）的表达急剧下降，而组织裂解液或膜部分的N-钙粘蛋白，桥粒斑蛋白和γ-连环蛋白的表达显着增加。左心室。STRING数据库分析表明，β-catenin与LRP6相互作用，但没有其他与ID相关的蛋白。我们的免疫沉淀分析表明，LRP6与Cx43，N-钙黏着蛋白和γ-连环蛋白强烈相互作用，而与β-连环蛋白弱相互作用，而与去氨铂丝无关。针对LRP6缺乏症，β-或γ-catenin向N-cadherin的募集增加了，但它们与Cx43的交互作用很小。总之，需要LRP6来维持ID结构的完整性和ID蛋白的平衡，并且LRP6与Cx43，N-钙黏着蛋白和γ-连环蛋白之间的相互作用可能与该过程有关。