ATP敏感性钾通道亚基突变(Kir6.1[V65M])在Cantu综合征肥厚心肌室性心律失常中的作用及机制研究

Cantu综合征是一种新型离子通道病，患者普遍有心血管缺陷并携带有编码KATP通道亚基基因功能获得性突变，但突变导致其临床表现的病理机制尚不清楚，亦无有效治疗方法。前期我们在Kir6.1[V65M]突变小鼠观察到血压降低、心肌肥厚及心律失常的发生。本项目拟深入研究该突变对肥厚心肌心律失常的影响及具体机制，结合前期研究基础，我们推测Kir6.1[V65M]突变引起的原始血管扩张、血压降低导致RAAS系统被激活，血管紧张素II作用于心脏AT1受体，激活下游PLC-PKC/IP3R通路，导致心脏结构重构和电重构。为证实该假说，我们将检测AngII-AT1R-PLC-PKC/IP3R通路的表达，同时应用shRNA技术干扰通路相关蛋白表达验证心脏表型能否被逆转。本项目将阐明Kir6.1[V65M]突变引起心脏重构的病理机制，以期为Cantu的防治提供依据并为离子通道突变相关心血管疾病防治提供新思路。

Cantu syndrome is a new type of ATP-sensitive potassium channelopathy. Cardiac defects are common clinical manifestations in Cantu patients who carry gain of function mutation of KATP channel. However, the pathologic mechanisms between these mutations and clinical presentations remain unclear and there is no effective treatment so far. In our early study, We observed low blood pressure, cardiac hypertrophy and ventricular arrhythmias in Kir6.1[V65M] mutant mice. The current project is proposed to further study the effect of Kir6.1[V65M] mutation on arrhythmia and discuss the specific mechanism, according to previous study we speculate that the vessel dilation and low blood pressure caused by Kir6.1[V65M] mutation result in RAAS system activation. AngII binds to AT1 receptor in the heart, leading to activation of PLC-PKC/IP3R pathway and cardiac remodeling. To confirm this hypothesis, we will examine the expression of AngII-AT1R-PLC-PKC/IP3R pathway. Meanwhile, shRNA technology will be used to interfere the protein expression of AngII-AT1R-PLC-PKC/IP3R pathway to verify whether the cardiac phenotypes can be reversed. This project will elucidate the pathological mechanism of cardiac remodeling caused by Kir6.1[V65M] mutation, so as to provide evidence for the prevention and treatment of Cantu and provide new ideas for the prevention and treatment of cardiovascular diseases related to ion channel mutation.