CircRNA9920/miR-22-3p/SIRT1在阿托伐他汀钙调控动脉粥样硬化血管平滑肌细胞异常增殖中的作用及机制研究

Atherosclerosis is the most common and dangerous cardiovascular disease, mainly characterized by the abnormal proliferation of Vascular smooth muscle cells (VSMCs). CircRNA is a class of non coding RNA with covalent closed structure. Our previous study found that the expression of circRNA9920 increased significantly in rat vascular smooth muscle cells(VSMCs) after PDGF-BB treatment, while its expression decreased significantly after combined treatment of atorvastatin calcium and PDGF-BB. Overexpression of circRNA9920 could increase the expression of SIRT1, and the expression of SIRT1 decreased after the silence of circRNA9920. In addition, according to bioinformatics analysis, the binding sites of miR-22-3p were found on both circRNA9920 and SIRT1. We hypothesized that atorvastatin calcium inhibits the expression of circRNA9920 and releases miR-22-3p via ceRNA mechanism to promote the degradation of SIRT1, thus inhibiting the abnormal proliferation of VSMCs. The goal of this project is to investigate the relationship and roles of circRNA9920, miR-22-3p and SIRT1 on abnormal proliferation of vascular smooth muscle in atherosclerosis during treatment of atorvastatin calcium, and further explore its mechanism. This project will deepen our understanding of the VSMCs phenotype transformation induced by PDGF-BB and the mechanism of atorvastatin calcium on atherosclerosis, which will provide a theoretical basis for the clinical application in atherosclerosis.

动脉粥样硬化是心脑血管事件的共同病理基础，主要表现为血管平滑肌细胞（VSMCs）异常增殖、迁移和表型转化。CircRNA是一类闭合非编码RNA，申请者发现在血小板源性生长因子诱导的异常增殖的VSMCs内，circRNA9920表达显著增加，而阿托伐他汀钙（ATV）联合处理能抑制其表达。CircRNA9920能正调控SIRT1表达，生信分析表明circRNA9920和SIRT1上都有miR-22-3p的结合位点，我们推测circRNA9920以ceRNA方式调控miR-22-3p对SIRT1的降解，从而介导ATV抑制VSMCs的异常增殖过程。本项目拟在VSMCs中深入分析circRNA9920/miR-22-3p/SIRT1在ATV抑制VSMCs异常增殖、迁移和表型转化中的作用及机制，并在动物模型中对其进一步验证，为动脉粥样硬化等心血管疾病的临床防治提供新的理论依据。

我们在已结题项目“CircRNA9920/miR-22-3p/SIRT1在阿托伐他汀钙调控动脉粥样硬化血管平滑肌细胞异常增殖中的作用及机制研究”的研究中，发现了阿托伐他汀钙能抑制PDGF-BB诱导的VSMCs的增殖、迁移和表型转化。CircRNA9920和SIRT1促进了在动脉粥样硬化组织和PDGF-BB诱导的大鼠原代VSMCs的增殖和迁移能力的增强，以及收缩型标志蛋白的表达的下降。此外，阿托伐他汀钙通过下调VSMCs中circRNA9920的表达水平，进一步调控了SIRT1的表达，从而抑制了动脉粥样硬化血管平滑肌细胞的异常增殖和表型转化。在项目执行过程中，我们进一步延伸了项目内容，获得了新的生长点，进一步发现了Pax9通过增加Shh的表达，促进PDGF-BB诱导的VSMCs的异常增殖、迁移和表型转化的机制。