敲除RGS2调节血管紧张素II信号通路对主动脉夹层的保护作用及机制

Angiotensin II is implicated in the development of aortic aneurysm and dissection. Thus, AngII is considered as breakthrough in treatment of aortic dissection. However, there was a paradox in aortic dissection about TGF-β abnormal treatment by AngII. In our previous research we found: 1. Down-regulated TGF-β signaling added up-regulated AngII signaling have synergistic effect, which exacerbate aortic dissection. 2. The possible mechanism is increase RGS2. 3. Inhibition p-SMAD3 could increase RGS2 expression. We hypothesized that high-level RGS2 lead basal tension decreases in VSMC. And stress of blood pressure result in MAPK pathway and T cell over-activation, which accelerate aortic dissection. In this project, we will:1. Using VSMC/T cell specifically RGS2 knockout mice to establish the aortic dissection model, study the effect and mechanism after RGS2 knockout in different cells; 2. To elucidate the regulation of SMAD3 to RGS2 expression, certify the interaction between TGF-β signaling and AngII signaling pathway. This project will improve the pathogenesis of aortic dissection, and provide experimental evidence of new therapeutic target or strategy.

研究证实，血管紧张素II（AngII）通路是主动脉夹层的重要致病机制，也是治疗主动脉夹层的突破口。但目前干预AngII治疗 TGF-β通路异常的主动脉夹层理论存在悖论。我们的前期研究发现：1.降低的TGF-β通路与升高的AngII通路之间存在某种协同关系，导致主动脉夹层进展；2.其机制可能与RGS2表达增高相关；3.抑制SMAD3磷酸化，增加RGS2蛋白表达。我们推测，RGS2蛋白高表达导致主动脉中层平滑肌基础张力降低，在压力应激下MAPK途径过度激活、病变局部T细胞过度活化，促进主动脉夹层发生。本课题将：1.建立RGS2平滑肌细胞/T细胞特异性敲除小鼠主动脉夹层模型，研究不同细胞组分RGS2敲除后对主动脉夹层的保护效应及机制；2.阐明SMAD3对RGS2的调控机制，证明TGF-β通路与AngII通路之间的相互作用。本课题为完善主动脉夹层发病机制，探讨可能的治疗靶点和思路提供实验依据。

研究证实，血管紧张素II（AngII）通路是主动脉夹层的重要致病机制，也是治疗主动脉夹层的突破口。AngII与TGF-β通路之间的相互作用成为主动脉夹层的研究热点和难点。在本项目中，我们证明与RGS2功能具有协同作用的PKM2对主动脉夹层的保护性效应，使用TEPP-46激活PKM2明显降低小鼠胸主动脉夹层的发生。提示AngII通路在小鼠胸主动脉瘤中的主导作用和作为潜在调控靶点的可能性。同时，我们使用单细胞测序技术对马凡小鼠升主动脉平滑肌细胞进行细胞来源亚群分类，了解不同亚群TGF-β信号通路激活情况，从而揭示在主动脉瘤中，不同细胞AngII与TGF-β通路之间的作用关系。同时，我们在收集临床标本过程中，借助完善的病例登记系统，分析夹层相关高危因素，为今后临床治疗该类疾病提供相关依据。