室旁核中内皮素-1在高血压大鼠交感神经过度激活调控作用的分子机制研究

Hypertension is a disease with high morbidity and low therapeutic effects. Although recent studies demonstrate different degrees of sympathetic hyperactivity in various types of hypertension, the underlying mechanisms are still unclear. Other groups and our lab indicated that endothelin-1 in the central nervous system may involve in sympathetic hyperactivity,which needs to be further clarified. We hypothesized that endothelin-1 levels of the central nervous system were elevated in hypertensive states, then it increased superoxide anion levels by mediating ETA and / or ETB receptor, which resulted in sympathetic hyperactivity. In the proposed study, we will therefore investigate the role,molecular mechanisms and the downstream signal pathways of endothelin-1 in the PVN in mediating sympathetic hyperactivity in hypertensive rats from overall to cell and molecule level and will intervene the key targets of endothelin-1 by using drug and RNA interference methods to study its effects on the prevention and treatment of hypertension. The proposed study may provide insight into the novel molecular mechanisms of endothelin-1 in the PVN in sympathetic overactivation in hypertension, clarify why endothelin receptor antagonists exhibit good therapeutic effects for refractory hypertension, as well as provide new research targets for prevention and treatment of hypertension.

高血压病发病率高且治疗效果不够理想，目前研究发现各种类型的高血压均有不同程度的交感神经活动过度增强，但其机制尚不清楚。国外学者和我们前期研究提示中枢内皮素-1可能在交感神经过度增强和血压的中枢调控中起重要作用，需要进一步阐明。我们假设高血压状态下心血管调节关键中枢室旁核内皮素-1水平升高，通过内皮素A和/或B受体使得超氧阴离子水平升高，进而导致交感神经活动过度增强。本课题拟从整体、细胞和分子水平深入探讨室旁核内皮素-1在高血压大鼠交感神经过度激活中的调控作用、分子机制和下游的信号通路，用药物和RNA干扰的方法干预内皮素-1的关键靶点，研究其对高血压的防治作用。研究有望揭示高血压交感神经过度激活的中枢机制，发现内皮素-1在高血压发病中的关键分子机制，为防治高血压提供新的思路和对策。

高血压ET-1活性过度增强是其恶化和进展的重要原因，但其对高血压状态中枢的影响和调节血压的机制尚不清楚。本项目以既往研究发现为基础，应用多种先进研究方法，从整体、细胞和分子水平综合研究ET-1在心血管重要中枢下丘脑PVN发挥作用的是通过ETA受体激活局部ROS增加，进一步引起神经发电增加和血压升高，为高血压病的防治提供新思路、新靶点和奠定实验基础。同时还和德国杜伊斯堡-埃森大学合作拓展研究了高血压中风的免疫和外泌体治疗的机制是抑制中性粒细胞和单核吞噬系统，增强淋巴细胞一系列损伤修复细胞因子的释放可以减轻神经损伤和改善血管重塑，为中风的治疗指明新的方向。本项目相关的研究成果已经申请了专利，如一种实时监测血压的动态降压装置、一种肾性高血压记忆合金夹和一种冠心病急救智能装置等，可以直接将基础研究成果转化临床，为病人带来福利，利国利民。