Exosome-YKL-40调控轴介导的EC/SMC间通讯在动脉粥样硬化中的作用及机制研究

The role of chronic inflammation of pathogen infection in atherosclerosis(AS) gain more and more attention recent years. Our study showed that plasma YKL-40 increased in the patients with carotid atherosclerotic stenosis(CAS) with pathogen infection compared with those without infection. Futher study indicated that YKL-40 increased the plaque instability，but its mechanism isn’t completely clear till now. We fould that vascular endothelial cell (EC)infected by cytomegalovirus(CMV) could secret exosome carried with miRNAs. When exosome was co-cultured with smooth muscle cell(SMC), the exosome could transfer to SMC and promote SMC proliferation，and YKL-40 expression in SMC was also increased. According to the results,we hypothesize that CMV-infected EC secrets exosome carried with miRNAs, which can communicate with SMC through regulating YKL-40 and then play an important role on the pathogenesis of AS. Therefore in this program, we plan to screen the specific miRNAs of exosome derived from CMV-infected EC, and investigate the role and mechanism of exosome derived-miRNAs and YKL-40 on the communication between EC and SMC as well as their role on the pathogenesis of AS. The results of this program will help give further new insights into the role of inflammation on AS and provide new possible target moleculars for early prevention and treatment for AS.

病原微生物感染所致炎症反应在动脉粥样硬化（AS）中的作用日益受到重视，我们前期证实病原微生物感染的颈动脉粥样硬化狭窄患者血清炎症因子YKL-40明显增高，且与斑块不稳定性有关，其机制目前尚不甚清楚。我们发现巨细胞病毒（CMV）感染血管内皮细胞（EC）后可分泌携载miRNAs的exosome；将exosome与血管平滑肌细胞（SMC）共培养，其可转运至SMC，并促进SMC增殖和YKL-40表达。据此提出假说：CMV感染EC可分泌携载功能性组分如miRNA的exosome与SMC发生通讯作用，其可能通过调控YKL-40介导AS的炎症机制，影响AS的发生发展。本项目拟进一步筛选CMV感染EC来源exosome特异性miRNAs，明确其在EC/SMC间的通讯作用及对YKL-40的调控机制，进而探讨它们在AS发生发展过程中的作用，为AS发病机制研究提供新思路，甚至提供可能的生物标记物及干预靶点。

病原微生物感染所致炎症反应在动脉粥样硬化（AS）中的作用日益受到重视，我们前期证实病原微生物感染的颈动脉粥样硬化狭窄患者血清炎症因子YKL-40明显增高，且与斑块不稳定性有关，其机制目前尚不甚清楚。本项目按照项目年度计划进行研究，完成了巨细胞病毒（CMV） 感染 EC 的 exosome 的抽提、鉴定以及 miRNA 测序及生物信息学分析及验证，初步筛选出了 CMV 感染 EC来源的差异表达 miRNAs，HCMV 感染能改变内皮细胞分泌的 exosomes 中所含的 miRNAs 成分，且HCMV 感染的内皮细胞分泌的 exosomes 能与 SMC 通信，促进其迁移能力增强。进一步我们选择差异表达的 miR127进行深入研究，结果显示miR127在不稳定性斑块中的表达增高且主要表达于巨噬细胞以及斑块内新生血管内皮细胞，体外巨噬细胞中过表达及干扰miR-127，结果显示miR-127-3p可能促进巨噬细胞的增殖从而加剧斑块的不稳定性。同时课题组进一步探讨了炎性因子 YKL-40 在 其中的可能作用和机制，结果提示YKL-40在动脉粥样硬化的早期，可以通过激活NF-κB信号通路，增强与炎症因子TNF-α的协同增强作用，刺激血管内皮细胞高表达粘附分子ICAM-1、VCAM-1，从而促进动脉粥样硬化早期斑块形成。该项目为 AS 的发病机制研究提供了新的线索和可能的干预靶点。

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