Elabela在交感神经激活和高血压发病中的作用与机制研究

Excessive sympathetic nervous activity plays a key role in the initiation and development of hypertension. The paraventricular nucleus (PVN) is an important integrative site in the control of cardiovascular activity, which is involved in the excessive sympathetic nervous activity of hypertension. Elabela (ELA) is a recently discovered bioactive peptide, which is required for heart development and signals via the orphan G protein -coupled receptor (APJ). We have found that PVN application of ELA induced sympathoexcitation and increasement in blood pressure, and the effects in the spontaneous hypertensive rats (SHR) is more significant. However, the underlying mechanism remains unknown. The study is based on our previous work, and explore the role and mechanism of ELA on sympathetic nervous activity in the hypertensive rats, and to determine signaling pathways and signaling molecules mediating the effects of ELA in vivo and in vitro.The aim of this study is to investigate the key target related to hypertension and explore the therapeutic effect through chronic experimental intervention. The study will illuminate the relationship between ELA in the PVN and the pathogenesis of hypertension, and provide new strategy for the prevention and treatment of hypertension.

交感神经活动过度增强在高血压病的发病和并发症形成中起到关键性作用。下丘脑室旁核（PVN）是调控心血管活动的重要中枢部位，与高血压病过度增强的交感神经活动密切相关。Elabela（ELA）是新发现的生物活性肽，作为血管紧张素1型受体相关蛋白（APJ）的内源性配体，在心脏的发育过程中起重要作用。我们最近发现大鼠PVN 注射ELA 可引起血压升高和交感激活效应，且高血压大鼠的效应更显著，但具体作用机制仍不清楚。本项目以既往研究为基础，探讨ELA 在交感神经活动的调控和高血压发病中的作用及其机制，确定介导ELA效应的信号转导途径和信号分子，找出与高血压发病密切相关的关键靶点，并深入研究干预关键靶点对高血压病的治疗作用。该研究不仅有助于阐明PVN 中ELA 与高血压病发病机制的关系，而且为防治高血压病提供新策略。

交感神经活性过度激活在高血压病发生、发展和并发症形成中起了极其重要作用，降低高血压病过度增强的交感神经活动是防治高血压病的重要策略之。下丘脑室旁核是整合和调控交感神经活动的重要核团之一。Elabela（ELA）是一种新发现的多肽，是血管紧张素受体样（APJ）受体的内源性配体。本研究旨在探讨室旁核ELA-21对自发性高血压大鼠（SHR）血压及交感神经活动的影响。实验在雄性Wistar-Kyoto大鼠（WKY）和SHR中完成。我们发现，SHR的室旁核中ELA表达上调。室旁核微量注射ELA-21可升高自发性高血压大鼠的肾交感神经活性（RSNA）、平均动脉压（MAP）、心率（HR）、血浆去甲肾上腺素（NE）和精氨酸加压素（AVP）水平。静脉注射ELA-21可显著降低WKY和SHR的MAP和HR，但只引起RSNA的轻微下降。室旁核中给予APJ拮抗剂F13A预处理消除了ELA-21对RSNA、MAP和HR的效应。静脉输注神经节阻断剂六甲铵和血管升压素 V1a受体拮抗剂SR49059可显著降低室旁核ELA-21对自发性高血压大鼠RSNA、MAP和HR的效应，而六甲铵和SR49059联合应用几乎完全消除室旁核中ELA-21的效应。ELA-21微量注射可升高室旁核中PI3K和Akt的磷酸化水平，而PI3K抑制剂LY294002或Akt抑制剂MK-2206几乎消除了ELA-21对RSNA、MAP和HR的效应。应用渗透泵在室旁核慢性输注ELA-21（4周）可引起正常血压的WKY交感神经系统显著激活、血压升高和AVP释放增多，并伴有心血管重塑。总之，我们发现了室旁核微量注射ELA-21可提高交感神经活性和血压，这是首次证明中枢的ELA在高血压中的作用。室旁核中ELA-21的升压作用是通过PI3K-Akt途径介导，交感神经激活和血管加压素释放两条途径共同发挥作用。我们的研究证实了自发性高血压大鼠室旁核中ELA表达上调，可能参与了高血压时血压的升高和交感神经激活机制。