FOXM1调控CD36表达诱导肌源性泡沫细胞形成的作用研究

Vascular smooth muscle cells (VSMCs) are the important origin of foam cells in atherosclerotic plaque, but the mechanism of smooth muscle-derived foam cells formation remains elucidated. CD36 plays very important roles in foam cells formation and development of atherosclerosis. FOXM1 is a newly found transcription factor of the Forkhead family, and FOXM1 probably regulates CD36 expression in VSMCs. Our preliminary results demonstrated that the expression of FOXM1 is up-regulated in atherosclerotic plaque and smooth muscle-derived foam cells. Therefore, we propose the following hypothesis: during the development of atherosclerosis, FOXM1 regulates CD36 expression and promotes smooth muscle derived-foam cell formation. In the present study, the expression of FOXM1 and CD36 in smooth muscle-derived foam cells will be observed in vitro, atherosclerotic mice models, and human atherosclerotic plaques with the technology of laser capture microdissection, immunofluorescence, and molecular biology. The role of FOXM1 in smooth muscle-derived foam cells formation and atherosclerosis development will be clarified with genetic or drugs means of activation or inhibition of FOXM1. Furthermore, the molecular mechanism of FOXM1 enhancing the transcription and expression of CD36 will be verified. Through this project, we expect to elucidate the mechanism of smooth muscle-derived foam cells formation, and provide a new strategy for preventing and treating atherosclerosis.

血管平滑肌细胞（VSMC）是动脉粥样硬化泡沫细胞的重要来源，但肌源性泡沫细胞形成的机制远未阐明。CD36在泡沫细胞形成及动脉粥样硬化发生中发挥关键作用。FOXM1是近年新发现的叉头框转录因子家族成员，VSMCs中CD36表达可能受FOXM1调控。预实验发现，动脉粥样硬化斑块及肌源性泡沫细胞中FOXM1表达增加。据此假设： 在动脉粥样硬化发生发展过程中，FOXM1通过转录调控CD36表达诱导肌源性泡沫细胞形成。本项目拟从细胞、动物及临床标本三个层次运用激光显微捕获、免疫荧光及分子生物学等技术检测肌源性泡沫细胞中FOXM1表达活化及CD36表达；利用基因工程手段或药物调控FOXM1表达，明确FOXM1在肌源性泡沫细胞形成及动脉粥样硬化发生发展中的作用；研究FOXM1通过调控CD36表达诱导肌源性泡沫细胞形成的分子机制。以期深入研究肌源性泡沫细胞形成的机制，为防治动脉粥样硬化提供新思路。

血管平滑肌细胞（VSMC）异常增殖和迁移是高血压、动脉粥样硬化及血管成形术后再狭窄等血管内膜增殖性疾病的共同重要机制。FoxM1是近年新发现的叉头框转录因子家族成员，特异性表达于增殖活跃的组织细胞，但其在VSMC异常增殖迁移中的作用及机制尚不清楚。本课题采用分子生物学技术及血管损伤模型，系统研究FoxM1促进VSMC增殖迁移及血管损伤后新生内膜形成的作用。研究发现，在体外培养的VSMC增殖迁移模型及大鼠颈动脉损伤模型中，FoxM1均可被显著诱导表达。过表达FoxM1可促进VSMC表型转换、增殖及迁移，相反，敲减内源性FoxM1则可抑制VSMC表型转换、增殖及迁移。与此相应，在大鼠颈动脉内皮损伤模型中过表达FoxM1可显著加重新生内膜形成，但敲减FoxM1则可显著抑制新生内膜形成。综上，本研究为进一步认识血管内膜增生性疾病的分子机制，将FoxM1作为该类疾病潜在的治疗靶标提供了新思路和相关实验佐证。