偏向性调节AT1受体新型疫苗在抗动脉粥样硬化中的作用和机制研究

Renin Angiotensin System (RAS) has been acknowledged to play important roles in atherosclerosis. Although lots of studies have shown that angiotensin II (AngII) type 1 receptor blockers(ARBs) can repress the progression of atherosclerosis, control effect of the disease is far from satisfactory in reality. It’s urgent to explore new therapies. Recently, we have initially developed a novel vaccine, ATRQβ-001, which is aimed at the second extracellular loop of angiotensin II type 1 receptor(AT1R). Preliminary studies have evidenced that the vaccine can inhibit the pathological progression of atherosclerosis with some characteristics different from ARBs. First, no feedback activation circulating or local RAS was observed in ATRQβ-001–vaccinated animals. Second, antibodies produced after vaccination can suppress phosphorylation of ERK1/2 induced by Ang II without affecting elevated Intracellular calcium ion concentration, and they don’t influence binding of Ang II to the receptor. Further studies indicated that the vaccine may function via PPARγ pathway. So we have confidence to hypothesize that the ATRQβ-001 vaccine can exerts therapeutical effects against atherosclerosis and mechanisms include following: on the one hand, anti–ATRQβ-001 antibodies can biasedly regulate functions of AT1R and inhibit vascular remodeling as well as Gi activation induced by Ang II; on the other hand, Gq activation mediated by Ang II being reserved, the antibodies can manipulate PPARγ pathway by faciliating β-arrestin. We hope this study can provide new ideas and methods on biased regulation of AT1R and lay the foundation of further immunotherapy of chronic diseases.

肾素血管紧张素系统（RAS）在动脉粥样硬化（AS）中发挥重要作用，血管紧张素1型受体（AT1R）阻断剂（ARB）能抑制AS进展，但AS的控制效果欠佳，需要新的治疗方法。我们在国际上率先研制出针对AT1R胞外第二环的新型疫苗ATRQβ-001，前期研究表明疫苗能抑制AS进展，但和ARB有所不同：1、疫苗不反馈激活RAS；2、疫苗免疫生成抗体不影响血管紧张素Ⅱ（AngⅡ）和受体结合，但能抑制AngⅡ诱导的ERK1/2磷酸化，且不影响胞内钙离子浓度升高，进一步研究表明疫苗显著影响血管PPARγ通路。由此提出假说：疫苗免疫生成抗体能够偏向性调节AT1R功能，一方面抑制AngⅡ介导的Gi活化和血管重构，另一方面保留AngⅡ对Gq通路的活化，通过激活β-arrestin调控PPARγ通路，综合两方面机制发挥抗AS作用。我们希望该研究能为偏向性调控AT1R提供新的思路的方法，也为慢病的免疫治疗奠定基础。

动脉粥样硬化（AS）是冠心病、脑卒中的主要病理基础，是人口死亡的主要原因。肾素血管紧张素系统（RAS）在动脉粥样硬化中发挥重要作用，血管紧张素Ⅱ（AngⅡ）和血管紧张素1型受体（AT1R）结合，介导血管炎症，促进动脉粥样硬化进展，尽管目前临床上有血管紧张素转化酶抑制剂（ACEI）和血管紧张素受体阻断剂（ARB）用于抗动脉粥样硬化治疗，但动脉粥样硬化的控制仍然不尽如人意，尤其是ARB使用后导致的RAS系统反馈激活也削弱了药物的治疗作用。在我们前期的工作中，我们在国际上首次报道了针对AT1AR胞外第二环的疫苗ATRQβ-001，该疫苗可以阻断AT1R但不引起RAS反馈激活，其机制不明。在该课题资助下我获得了和ATRQβ-001相同靶点的单克隆抗体McAb-ATR，通过一些列实验证明了1、McAb-ATR抗体对高脂喂养ApoE-/-小鼠动脉粥样硬化有保护作用，且不反馈激活RAAS系统；2、McAb-ATR抗体促进巨噬细胞表型从M1到M2的转换；3、McAb-ATR抗体特异性和AT1AR结合且偏向性调节AT1R功能；4、McAb-ATR抗体发挥功能依赖β-arrestin2。该课题的结果阐明了McAb-ATR抗体发挥作用的机制，发现了ATRQβ-001疫苗/McAb-ATR抗体区别于ARB的特点，给G蛋白偶联受体（GPCR）提出了全新的调控方式，一方面为疫苗的进一步临床转化奠定基础，也为GPCR药物研发提供全新思路。