piRNA介导的DNA甲基化在血管平滑肌细胞和动脉粥样硬化中的作用及机制研究

The proliferation and phenotype transformation of vascular smooth muscle cells (VSMC) play an important role in atherosclerosis (AS), and they are the main factors determining the stability of AS plaques and fibrous caps. How to regulate and stabilize the pathological proliferation of VSMC is a key problem, and it is of great significance to explore the potential important regulatory factors. Through high throughput sequencing, we have found that the small molecular nucleic acid piRNA plays an important role in this process, but the molecular mechanism is still unclear. Further studies show that piRNA-1903 is highly expressed in cardiovascular system, which is down regulated in AS and significantly promotes VSMC proliferation and migration. We speculate that it may play a role in the promoter region of AS sensitive gene hnRNP-K and mediate VSMC pathological proliferation through DNA methylation. These findings will be the first time to connect piRNA-DNA methylation-VSMC phenotype transformation-AS signal axis together, and try to investigate the biological effects of piRNA in fiber hat stable, reveal the molecular mechanism for the regulation of piRNA in AS plaque formation. Finally, we try to research the potential function of piRNA from animal and clinical level. This study will provide a new theoretical basis for the occurrence and development of piRNA regulation in AS, and offer a new target for the prevention and treatment of AS.

血管平滑肌细胞(VSMC)的增殖与表型转换在动脉粥样硬化（AS）中具有重要作用，是决定AS斑块和“纤维帽”稳定的主要因素。如何调控和稳定VSMC的病理性增殖是关键科学问题，探索潜在重要的调控因子具有重要意义。通过高通量测序，我们发现小分子核酸piRNA在其中发挥重要功能，但具体机制尚不清楚。进一步研究表明piRNA-1903在心血管中特异高表达，在AS病理过程中下调并显著促进VSMC的增殖和迁移，我们推测其可能作用于AS敏感基因hnRNP-K的启动子区，通过甲基化介导VSMC的病理性增殖。上述发现首次将piRNA—DNA甲基化—VSMC表型转换-AS信号轴联系起来，拟明确piRNA调控“纤维帽”稳定的生物学作用，揭示piRNA甲基化调控AS斑块形成的分子机制，在动物和临床水平上深入阐释piRNA调控AS的潜在功能，为piRNA调控AS的发生发展提供新的理论基础，为AS的防治提供新的靶点。

血管平滑肌细胞(VSMC)的增殖与表型转换在动脉粥样硬化（AS）中具有重要作用，是决定AS斑块和“纤维帽”稳定的主要因素。如何调控和稳定VSMC的病理性增殖是关键科学问题，探索潜在重要的调控因子具有重要意义。本项目结合高通量测序，筛选和分析到piRNA-1903是其潜在的重要分子。进一步研究表明piRNA-1903在心血管中特异高表达，在AS病理过程中下调并显著促进VSMC的增殖、迁移和表型转换。分子机制方面，我们首次发现piRNA-1903可以结合AS敏感基因hnRNP-K的启动子区并改变其甲基化水平，其中DNMT1发挥了主要的调控作用。本项目首次将piRNA—DNA甲基化—VSMC表型转换-AS信号轴联系起来，明确了piRNA调控“纤维帽”稳定的生物学作用，为AS的发生发展提供新的理论基础，为AS的防治提供了表观遗传方向的新靶点。