Elabela-APJ轴调控Akt/Sox17信号在高血压血管内皮损伤及功能紊乱中的作用及机制研究

Hypertension is seriously harmful to human health and is closely related to vascular endothelial injury and dysfunction. In the preliminary study, we used pulse wave velocity to detect vascular function (Advanced Materials, 2017), and we observed that Apelin had certain hypotensive and cardiovascular protective effects. Elabela (ELA) was found as a new type of endogenous ligand of Apelin receptor (APJ) in recent years, which mainly expressed in vascular endothelial cells. ELA could regulate blood pressure and blood vessel function, but its role on the vascular endothelial injury and dysfunction of hypertension is not clear. Based on our previous findings, we are going to investigate the relationship among ELA, Apelin, APJ, Sox17 and vascular function in hypertensive patients. The aim of his study is to demonstrate the effect of ELA-APJ axis on blood pressure, endothelial Akt/Sox17/eNOS signal, apoptosis, oxidative stress and inflammation by using hypertensive animal model and cultured endothelial cells. The impact of ELA interference on its regulation function and mechanism is also discussed. This project is designed to clarify the mechanism of ELA in protecting hypertensive endothelial function. It is hopeful to find new targets for early prevention and treatment of hypertension.

高血压严重危害人类健康，与血管内皮损伤及功能紊乱密切相关。前期研究工作我们运用脉搏波传导速度检测血管功能（Advanced Materials，2017），同时我们观察到Apelin具有一定的降压和心血管保护作用。Elabela（ELA）是近年来发现的Apelin受体（APJ）的新型内源性配体，主要在血管内皮细胞表达，能调节血压及血管功能，但其对高血压介导的血管内皮损伤及功能紊乱是否有调控作用尚不清楚。在此基础上，本课题拟分析高血压患者ELA、Apelin、APJ、Sox17与血管结构功能损伤的相关性；采用高血压模型动物和细胞进行体内外实验，探讨高血压状态下，血管内皮Akt/Sox17/eNOS信号、凋亡、氧化应激、炎症反应及内皮功能的改变及ELA干扰对其调控作用和机制，以阐明ELA-APJ轴保护内皮细胞功能的机制，为高血压血管损伤早期防治找到新靶点。

Elabela是新近发现的apelin受体（APJ）的一种新的内源性配体，在心血管疾病如心肌梗死、高血压和心力衰竭中发挥着重要作用。既往研究表明，Elabela/APJ系统调控心脏及血管的发育及功能，因此对维持血管稳态具有重要作用。本项目探讨了Elabela对血管炎症、氧化应激、凋亡的影响及可能的机制，以及急性冠脉综合征患者内源性Elabela水平用于冠状动脉狭窄严重程度判断的临床应用价值。研究结果发现：外源性Elabela显著减轻血管紧张素II（Ang II）诱导大鼠主动脉血管外膜成纤维细胞中炎症反应、氧化应激及凋亡，同时增加了成纤维细胞生长因子21（FGF21）及血管紧张素转换酶2（ACE2）的表达水平；利用siRNA下调Elabela基因表达后，促进了Ang II诱导的成纤维细胞迁移，增加了IL-1β，IL-6，MCP-1及TNF-α等炎症因子的表达，抑制了FGF21及ACE2的表达；利用siRNA下调FGF21基因表达后，显著减弱Elabela对Ang II诱导的炎症反应、氧化应激及凋亡的保护效应。以上结果表明，Elabela/APJ系统通过作用于FGF21/ACE2信号通路，发挥抗炎症反应、抗氧化应激及抗凋亡的作用。临床试验结果显示：急性冠状动脉综合征患者血浆Elabela水平较正常对照人群显著升高。内源性Elabela水平升高与冠状动脉狭窄的严重程度密切相关，可能参与急性冠状动脉综合征的发病机制，有待进一步研究。Elabela可能是预测血管损伤的新的生物标志物。