CFTR与血管紧张素Ⅱ 1型受体结合调控高血压血管重构及药物影响

AngⅡ激活AT1R信号通路是防治高血压血管重构最重要的药物靶标。在国自然基金支持下，我们前期在高血压病人和高血压动物模型上发现，血管平滑肌CFTR表达随血压升高而下降，CFTR基因敲除促进血管平滑肌细胞增殖和AngⅡ诱导高血压过程中的脑血管重构。CFTR与AT1R在细胞膜上直接结合，过表达CFTR促进AT1R内化。本项目拟阐明CFTR通过与AT1R相互作用，调控AT1R表达、AT1R内化及细胞增殖的机制；并在整体模型上探讨CFTR与AT1R信号在高血压血管重构中内在相互关联的机制，及用药物干预CFTR-AT1R结合后对血管重构的影响。本研究将阐明血管平滑肌CFTR新功能，提出CFTR是调控AT1R信号内源性稳定分子的新观点，并从CFTR-AT1R蛋白复合体这一新角度，为寻找防治高血压血管重构新靶点提供线索。

Ang II activating signaling pathway mediated by angiotensin type I receptor (AT1R) is an important drug target against hypertensive vascular remodeling. Our preliminary data found that, as blood pressure increased, the mRNA and protein levels of CFTR chloride channel decreased in the abdominal artery from hypertension patients and arteries from animal hypertension animal models with different mechanisms. In mice, deletion of CFTR promoted Ang II–induced increase in blood pressure, basilar arterial remodeling and proliferation of vascular smooth muscle cells (VSMCs). In VSMCs, knockdown of CFTR promoted Ang II-induced proliferation and upregulated proliferative signaling pathway downstream of AT1R, whereas overexpression of CFTR did the opposite. We also found that CFTR directly binds to the AT1R on the cell membrane. The overexpression of CFTR promotes the co-transport of CFTR-AT1R into cells. The present project aims to clarify the interaction between CFTR and AT1R, and how this interaction interferes with AT1R-mediated VSMC proliferation signaling pathway and thus regulates VSMC proliferation. Moreover, we will investigate the functional role of CFTR in hypertension-induced arterial proliferative remodeling in CFTR knockout mice. This study will reveal the new function of CFTR and raise the possibility that CFTR may be a key molecule regulating AT1R signal transduction through the formation of CFTR-AT1R heterodimers. This project will also provide important evidence to identify CFTR as a new therapy target against hypertensive vascular remodeling.