热休克蛋白A12B-核受体RORγT信号通路对高血压血管内皮功能的调控作用及机制

Endothelial cells play a key role in arterial vasoconstriction, and their dysfunction is closely related to hypertension. Our previous studies have shown that heat shock protein A12B (HspA12B) specifically expressed in endothelial cells plays a protective role in reducing myocardial inflammation through PI3K/Akt pathway. Normal blood pressure fluctuation varies with the biorhythm, and our preliminary experiment results showed that the expression of RORγT increased significantly and HspA12B decreased in spontaneously hypertensive rats. Further experiment data also found that oxidative stress significantly increased and endogenous nitric oxide synthase (eNOS) significantly decreased when knocking down HspA12B. Therefore, we speculate that HspA12B improves endothelial function through PI3K/Akt pathway. On the other hand, HspA12B regulates endothelial cells and endothelium-dependent vasodilation via the mechanism of nuclear receptor RORγT-reactive oxygen species cluster-eNOS, which plays an important role in the occurrence and development of hypertension. The aim of this study is to explore the regulatory mechanism of HspA12B and nuclear receptor RORγT on vascular endothelial function in hypertension by means of immuneprecipitation, immunofluorescence and other molecular biological methods in animal models, vascular tissues and cells. This research may provide a new target for clinical treatment of hypertension.

内皮细胞在动脉血管舒缩功能中起关键作用，内皮功能紊乱与高血压密切相关。申请人前期研究表明，特异性表达于内皮细胞的热休克蛋白A12B（HspA12B）通过PI3K/Akt通路，在心肌炎症中发挥保护效应。正常血压波动随生物钟而变化，预实验发现，在自发性高血压大鼠血管中，生物钟核受体RORγT表达显著升高，同时HspA12B表达降低；进一步实验还发现，敲降HspA12B，氧化应激显著升高，内源性一氧化氮合酶（eNOS）表达降低。因此，我们推测HspA12B通过PI3K/Akt通路改善内皮功能；另一方面，通过RORγT-活性氧簇-eNOS机制，调控血管内皮细胞信号通路和内皮依赖的血管舒张功能，在高血压发生发展中起重要作用。本研究拟从动物模型、血管组织及细胞层面，应用免疫共沉淀、免疫荧光等分子生物学手段，探索HspA12B-核受体RORγT对高血压血管内皮功能调控机制，为临床治疗高血压提供新靶点。

血管内皮细胞功能紊乱与高血压密切相关，血管内皮舒缩功能异常及炎症介质破坏了内皮完整性，是高血压发病的重要的因素。研究结果表明，特异性表达于内皮细胞的热休克蛋白A12B（HspA12B）通过PI3K/Akt通路，在心肌炎症中发挥保护效应，同时内源性一氧化氮合酶（eNOS）表达升高也是发挥了保护效应。正常血压波动随生物钟核受体而变化，核受体共抑制因子1(NCoR1)是调控细胞存活和死亡信号的关键因子，我们研究结果发现NCoR1在小鼠心脏中高度表达，并在急性心肌损伤后显著下调。并且发现心肌细胞特异性NCoR1敲除后心肌细胞线粒体功能发生障碍，且促进了炎症通路活化。在自发性高血压大鼠血管中，生物钟核受体RORγT表达显著升高，同时HspA12B表达降低；进一步实验还发现，敲降HspA12B，氧化应激显著升高，内源性一氧化氮合酶（eNOS）表达降低。另一方面，通过RORγT-活性氧簇eNOS机制，调控血管内皮细胞信号通路和内皮依赖的血管舒张功能，在高血压发生发展中起重要作用。HspA12B-核受体RORγT对高血压血管内皮功能调控机制，为临床治疗高血压提供新靶点。