AT1R降压疫苗对血管重构的调控机制研究

Hypertension is the most important risk factor of stroke and coronary heart disease. It is of great significance to further study mechanism of vascular remodeling in hypertension and look for new treatment technology. We invented the AT1R hypertension vaccine. This project will study the regulatory mechanism of AT1R hypertensive vaccine on vascular remodeling. We hypothesized: AT1R hypertension vaccine regulates AT1R allosterism, and is a positive regulator of ACE2-Ang (1-7)-MasR axis, blocking allosteric activation of AT1R by AngII, promoting the heterodimerization of AT1R/APJ, AT1R/MasR and AT1R/TRPV4. These heterodimerization is bias to the pathway activation of APJ, MasR and TRPV4. Meanwhile, AT1R hypertension vaccine produces Th2-bias immune response, down-regulates AT1R homodimer formation of inflammatory cells, and reduces the chemokine expression and adhesion molecules of monocytes, inhibiting the migration and infiltration of T lymphocyte in target organs. And also, T cell associated inflammation cytokine production are reduced. Collectively, the overall effect is of weakening remodeling pathway, and thus plays a more significant and more long-lasting protective effect to the target vessels, providing the theory foundation for establishing novel technology of vascular-regulation research and developing new-style hypertension vaccine.

高血压是导致脑卒中和冠心病的主要危险因素，深入研究高血压的血管重构机制和寻找新型的高血压治疗技术具有重要意义。我们发明了AT1R降压疫苗，本项目将利用学科交叉手段阐明该抗血管重构新技术的作用机制：AT1R降压疫苗通过调节AT1R变构和正向调节ACE2-Ang（1-7）-MasR轴，阻滞AngII激动AT1R后该受体的活化性变构，促进AT1R-APJ、AT1R-MasR及 AT1R-TRPV4异二聚化及通路偏向性激活；并通过主导Th2亚型免疫应答，下调炎症细胞AT1R同源二聚体形成，减少趋化因子及粘附分子表达，抑制T淋巴细胞的靶器官迁移浸润，降低T细胞相关炎症细胞因子的产生，整体削弱重构效应，从而发挥更长效的更显著的靶血管保护作用，为建立血管调控研究新技术及开发降压疫苗新型治疗技术奠定理论基础。

我们发明了AT1R降压疫苗。本项目：1）在糖尿病肾病、高血压肾病、动脉粥样硬化及心肌梗死四种动物模型上确证了AT1R疫苗的保护效应及对RAS双轴的调控作用，证明AT1R疫苗是一种新型的RAS调节剂；2）明确了AT1R疫苗关键作用位点182Phe和184Tyr，同时阐明了AT1R疫苗偏向性抑制AT1R/β-arrestin2信号通路改善血管重构的机制；3）揭示了AT1R疫苗新颖的免疫应答方式。与ARB类药物相比，AT1R疫苗全面调节RAS双轴，克服了ARB反馈激活RAS系统的缺点，并且其偏向性抑制AT1R/β-arrestin2信号通路实现了对AT1R更为特异性的调节，为治疗性降压疫苗及VLP载体疫苗的发展应用提供了充分的药理及免疫理论基础。