室旁核硫化氢通过Nrf2通路抑制高血压前期发生发展的机制研究

内源性硫化氢生成障碍是高血压病因之一，且硫化氢广泛分布于神经系统，然而下丘脑室旁核硫化氢在高血压前期的作用及其机制尚不清楚。本研究采用处于高血压前期的自发性高血压大鼠和盐敏感性大鼠，采用微型渗透泵经双侧室旁核给予硫化氢合成酶CBS激动剂、抑制剂或硫化氢缓释供体，明确室旁核硫化氢在高血压前期的作用；采用血管紧张素II诱导室旁核神经元，给予CBS激动剂、CBS底物、Nrf2激动剂或载有敲减CBS基因、Nrf2基因的shRNA慢病毒，或同时给予硫化氢缓释供体，探讨硫化氢通过Nrf2通路抗炎和抗氧化作用的机制；采用经室旁核微量注射载有敲减CBS、Nrf2的shRNA慢病毒或条件性基因敲除脑内CBS的大鼠，验证室旁核硫化氢通过Nrf2通路减少活性氧簇和促炎细胞因子进而降低高血压前期交感神经活动和血压。本项目将阐明室旁核硫化氢通过Nrf2通路抑制高血压前期发生发展的机制，为高血压前期的干预提供新靶点。

The endogenous hydrogen sulfide production obstacle contributes to the pathogenesis of hypertension. Hydrogen sulfide distributes in the entire nervous system. Hydrogen sulfide has a wide range of physiological effects on the cardiovascular system, including regulation of the sympathetic activity and inflammatory reactions. However, the role of hydrogen sulfide in the hypothalamic paraventricular nucleus (PVN) during prehypertension remains unclear. In this study, we will investigate the effects of hydrogen sulfide on sympathetic nerve activity, oxidative stress and proinflammatory cytokines in prehypertension through conditional gene knockout, virus-based shRNA mediated gene knockdown, chronic bilateral PVN infusion, primary neuron culture and molecular biology techniques. We will utilize 3.5-week-old spontaneously hypertensive rats, Dahl salt-sensitive rats, cystathionine beta-synthase (CBS) conditional knockout rats and their control Wistar Kyoto (WKY) rats, SS-13BN rats and wild-type rats to determine whether PVN hydrogen sulfide has beneficial effects during the progress of prehypertension towards hypertension. In addition, we will investigate whether hydrogen sulfide reduces the production of reactive oxygen species (ROS) and proinflammatory cytokines through activating the nuclear factor-erythroid related factor 2 (Nrf2) pathway in vitro and in vivo. Then wild-type rats and CBS conditional knockout rats will be utilized to confirm the mechanism that hydrogen sulfide via the Nrf2 pathway indeed affects the progression of prehypertension. The successful completion of the present study will expand our knowledge about the pathogenesis of prehypertension and provide new potential targets for prevention of hypertension.