胆汁酸及其受体FXR调节血管张力的机制研究

Hypertension is a major disease which is serious threat to people's health. Previous research found that the plasma bile acid concentration in patients with hypertension was significantly higher. This result indicated that blood pressure is related to bile acid concentration .Bile acid is an important signal molecular, while farnesoid X receptor (FXR) is a bile acid receptor.FXR express in the blood vessel. The plasma hydrogen sulfide concentration in patients with hypertension was significantly lower.Preliminary study demonstrated that the concentration was significant lower in the FXR gene knockout (FXRKO) mice than that in WT mice. We hypothesized that bile acid relaxes blood vessels directly by activating FXR ,and increases the synthesis of hydrogen sulfide.We will study the mechanism of bile acid and FXR in the regulation of vascular tension in the FXRKO and cholestasis model mice、vascular and cultured smooth muscle cells .This study will demonstrate the critical roles of bile acid in blood pressure regulation, and reveal its relation with the pathogenesis of hypertension.?????

高血压是严重威胁人民健康的重大疾病，原发高血压患者血清总胆汁酸浓度增高，提示胆汁酸与高血压有关。胆汁酸是重要的信号调节分子，FXR是胆汁酸受体,FXR表达于血管。前期实验发现注射胆汁酸CDCA能显著降低血压，胆汁淤积小鼠血压下降。有研究表明高血压患者血中硫化氢降低。我们发现FXR 基因敲除小鼠血清硫化氢浓度减低，硫化氢能舒张血管，因此我们提出假说：胆汁酸是内源性降压物质，胆汁酸主要通过激活FXR，增加硫化氢合成，舒张血管。本课题旨在探讨胆汁酸及FXR对血管张力的影响和机制，本项目将在FXR基因敲除小鼠、胆汁淤积小鼠、离体血管和血管平滑肌细胞上, 研究胆汁酸激活FXR,调节硫化氢进而调节血管张力的机制。本课题对阐明胆汁酸调节血管的机制以及揭示高血压机制有重要意义。

本项目是基于临床报道高血压患者存在血清胆汁酸增加的现象，在动物模型上探索和研究胆汁酸及胆汁酸受体FXR（farnesoid X receptor）对血压的影响机制，深入揭示胆汁酸通过受体FXR调节血压的分子机制。本项目应用血压测定、分子生物学、生物化学等实验技术,在建立的喂食胆汁酸和胆汁酸淤积的动物模型上，明确喂饲胆汁酸激活FXR、敲除FXR基因以及胆汁酸升高等病理状态对血压的影响，阐明了这些模型上FXR通过调节肾脏水盐代谢而影响血压的作用机制。研究结果表明：注射胆汁酸引起血压下降是胆汁酸直接舒张血管引起的一种急性效应，而临床上观察到的高血压患者胆汁酸升高可能由于患者代谢异常引起的。慢性的胆汁酸升高通过激活受体FXR影响了肾脏的水盐代谢导致钠水潴留，进而影响血压。在高盐饮食动物模型和培养集合管细胞上的研究发现，FXR能增加肾脏集合管细胞的水通道和钠通道表达，导致肾脏对钠水的重吸收增加，引起钠水潴留，进而导致血压升高。胆汁淤积时，FXR通过调节H2S合成关键酶胱硫醚-γ-裂解酶和钠通道调节血压。项目的研究证明胆汁酸异常与血压升高之间确实存在因果关系，揭示了胆汁酸受体FXR参与调节血压的具体机制。本项目的研究有助于阐明胆汁酸在血压调节中的作用，初步揭示临床高血压患者胆汁酸异常对高血压病程的影响机制，并为高血压患者治疗和药物开发提供新的靶点。