中枢血管紧张素1-7抑制神经炎症在降低高血压交感神经亢进中的作用研究

Hypertension is characterized by sympathetic nerve system overactivity, which is closely related to its development and prognosis. It has been suggested that immune inflammatory process is associated with pathophysiological process of heart and vessels in hypertension. Contribution of neuroinflammation in the central nervous sysmtem to sympathetic hyperactivity of hypertension is poorly understood. Angiotensin 1-7 (Ang1-7), whose action is opposite to Ang II, is capable of leading to cardiovascular protection. It is suggested that central Ang1-7 is invovled in mediating central cardivocascular regulation. However, it is not clear if central Ang 1-7 depresses neuroinflammation in hypertension. Therefore, the overall goal of the application is to determine the mechanism respossible for the effect of central Ang 1-7 on neuroinflammation in the sympathetic center RVLM, and to further illustrate the significance of Ang 1-7 action in reducing the sympathetic overactivity in hypertension. Using acute or chronic experiments and RNA interfere techniques in the model of spontensively hypertensive rats, the project will be carried out: 1) to determine the contribution of neuroinflammation-induced oxidative stress in the RVLM to sympathetic overactivity in hypertension; 2) to determine mechanism of anti-neuroinflammation in the RVLM produced by Ang1-7, and to clarify the significance of the Ang1-7-induced anti-neuroinflammation in reducing sympathetic overactivity in hyperternsion. The new evidence obtained from this project would provide new theory for contribution of neuroinflammation to sympathetic nerve system overactivity in hypertension. Furthermore, investigation of anti-neuroinflammation by central Ang1-7 would be helpful for searching for the therapeuatic strategy against cardiovascular diseases.

交感神经活动亢进是高血压的主要特征并与其发展和预后密切相关，免疫炎症反应参与高血压血管和心脏等病理改变，但高血压交感神经亢进与中枢神经炎症的关系并不明确。与血管紧张素II （AngII）作用相反的Ang1-7具有心血管保护作用，中枢Ang1-7并参与心血管活动的神经调控机制，但尚不清楚是否具有抑制高血压神经炎症的作用。因此，本研究总体目标是阐明Ang1-7对交感中枢头端延髓腹外侧区（RVLM）神经炎症的作用机制和意义。在高血压大鼠等模型上，通过急慢性整体实验和RVLM内基因干扰等技术方法将明确：1) RVLM神经炎症诱导的氧化应激在高血压交感神经亢进中的作用；2）中枢Ang1-7抑制RVLM神经炎症的作用特点和机制途径，及其在降低高血压交感神经亢进中的意义。研究结果为神经炎症在高血压交感神经亢进中的作用和意义提供新内容，探索Ang1-7抗神经炎症作用将为心血管疾病防治新策略研究提供新依据。

高血压病是心血管事件发生的重要机制，但其发病机制仍不清楚。近期研究提示炎症参与了神经源性高血压的发生发展。在中枢神经系统内也存在免疫炎症反应，称之为神经炎症（neuroinflammation）。延髓头端腹外侧区（rostral ventrolateral medulla，RVLM）是交感神经调控的关键中枢，在维持基础血压保持交感神经紧张性中具有重要作用。肾素血管紧张素系统（Renin-angiotensin system，RAS）过度激活在高血压的发病机制中发挥着重要作用。已有研究证实血管紧张素转化酶2（Angiotensin-converting enzyme 2， ACE2）在拮抗过度激活的RAS中发挥着重要的补偿机制，ACE2将Ang II和血管紧张素I（Angiotensin I，Ang I）转化成血管紧张素-1-7[Angiotensin-1-7，Ang-(1-7)]，而Ang-(1-7)通过与Mas受体相结合发挥与Ang II相拮抗的生物学效应。此外，有证据表明心血管调节中枢RVLM内磷脂酰肌醇-3-激酶（Phosphoinositide-3 kinase，PI3K）通路参与了血压和中枢交感输出的调节。因此，本研究的主要研究目标是明确RVLM内PI3K通路在高血压神经炎症中发挥的作用，并探索异常的RAS对高血压神经炎症的影响是否与PI3K通路有关。本研究证实了：1）干扰RVLM内PI3K信号通路减弱高血压RVLM内神经炎症。2）干扰RVLM内PI3K信号通路减弱Ang II诱导的神经炎症和心血管功能异常。3）过表达ACE2抑制PI3K信号通路减弱高血压大鼠RVLM内神经炎症。通过以上的研究提示RVLM内PI3K/AKT通路激活介导的神经炎症导致高血压心血管功能异常，RVLM内干扰PI3K通路能抑制Ang II诱导神经炎症和心血管功能异常，而RVLM特异性过表达ACE2通过抑制PI3K/AKT通路活性减弱高血压RVLM神经炎症水平。本研究明确了PI3K通路介导的神经炎症参与高血压交感亢进，为高血压交感亢进的机制研究和防治策略提供了新思路。