MCPIP-1的去泛素化作用调控增龄性小鼠心房巨噬细胞-心肌细胞间电耦联重塑的作用及机制

Aging is the most vital risk factor of atrial fibrillation (AF), the abnormal electrical conduction which caused by fibrosis and myocardial apoptosis is the chief mechanism that contributes to age-associated AF. It has already been demonstrated in our previous studies that the atrial expression level of MCPIP-1 in aged AF dogs increased. Atrial fibrosis and apoptosis induced by MCPIP-1 may aggravate the electrical remodeling caused by aging. But the mechnism remain unclear. Some researches shows that macrophages connect with myocardial cells via connexin and facilitate intercellular electrical coupling. Meanwhile, it plays an important role in regulating electrical conduction between myocardial cells. In this project, transgenic mouse models which are overexpressed MCPIP-1 will be used to determine whether MCPIP-1 have the effect of aggravating age-associated macrophage-myocyte electrical coupling remodeling and to illuminate the mechanism. It also aims to reveal the importance of macrophage polarization status induced by MCPIP-1 in age-associated macrophage-myocyte electrical coupling remodeling.The myocardial cells and macrophages of which MCPIP-1 expressions are interfered by siRNA will be cocultivated to illuminate the mechanism of MCPIP-1 deubiquitination in macrophage-myocyte electrical coupling and to explore the molecular target during this process. All mentioned above will bring new ideas and new targets to benefit the prevent and treatment of age-associated AF. Furthermore, it not only has a crucial scientific significance but a clinical transformation and application value as well.

增龄是心房颤动（房颤）至关重要的致病因素，心房纤维化和细胞凋亡导致的电传导异常是增龄性房颤发生的主要机制。本课题组前期研究发现老龄房颤犬心房MCPIP-1表达上调，其诱导的心房纤维化和细胞凋亡加剧增龄导致的心房电重构，但机制不明。研究表明，巨噬细胞通过缝隙连接蛋白与心肌细胞电耦联，调节心肌细胞电传导。本课题拟利用心脏特异性过表达MCPIP-1转基因小鼠模型，明确MCPIP-1过表达是否具有加剧增龄性小鼠心房巨噬细胞-心肌细胞电耦联重塑的作用及其机制，揭示MCPIP-1诱导的巨噬细胞极化状态改变在增龄性小鼠心房细胞间电耦联中的重要性；基于siRNA干扰MCPIP-1表达的巨噬细胞与心房肌细胞体外共培养体系，阐明MCPIP-1的去泛素化作用调控心房巨噬细胞-心肌细胞间电耦联的机制，探寻MCPIP-1去泛素化作用的靶点，为增龄性房颤的防治提供新思路和新靶点，具有重要的科学意义和临床转化应用价值。

心房颤动(房颤) 是最常见的快速性房性心律失常，增龄是发生房颤的独立危险因素。电耦联重塑、结构重构、能量代谢重塑等心脏重构在房颤的发生发展过程中的发挥至关重要的作用。本研究通过应用房颤患者样本、房颤动物模型样本以及公共数据库确认了MCPIP1在房颤疾病中表达增高。本研究进一步通过构建CaCl2-Ach诱导的房颤模型，并通过注射腺病毒实现MCPIP1在体水平的敲低及过表达，并探索在MCPIP1功能获得或丢失的条件下，房颤中电重塑、结构重塑、能量代谢重塑表型的变化及分子机制。结果表明作为去泛素化酶和RNA酶的MCPIP1可以通过增强自发性房颤的负荷，增加了心房的电不稳定性，促进了房颤的诱发，同时加剧了心房的扩张，促进了心房间质纤维化，增强增龄性的心房重塑，其分子机制与Wnt/β-catenin信号通路的激活有关，此外，过表达MCPIP1加剧线粒体形态的异常、功能的损伤以及糖脂转运失调，进一步构建房颤易感性底物。而激活SIRT1可以恢复MCPIP1诱导的心房能量代谢损伤，提示着MCPIP1作为增龄性房颤的重要易感分子可以通过至少三种途径加剧心房重构参与房颤从而为揭示增龄性房颤的发生发展新机制提供了初步理论基础。