hnRNPA1对血管平滑肌细胞分化和表型转换及损伤诱导的内膜新生的作用及机制研究

Both adventitial stem/progenitor cell differentiation into vascular smooth muscle cells and vascular smooth muscle cell phenotypic switching participate in vascular injury, repair and pathological remolding. A molecule that can promotes stem/progenitor cell dfferentiation into smooth muscle cells and inhibit mature smooth muscle cell phenotypic modulation after vascular injury might be a promising therapy for cardiovascular disorders, such as atherosclerosis and restenosis. we have revealed the involvement of hnRNPA1 in smooth muscle cell differentiation from embryonic stem cells. In this project, we will investigate: 1.Whether hnRNPA1 can promote stem/progenitor cell differentiation into functional mature smooth muscle cells. 2.Whether hnRNPA1 can modulate smooth muscle cell phenotype by repressing its proliferation and migration, and its underlying mechanisms. 3.Whether hnRNPA1 affects injury-induced carotid artery neointima formation. 4.How hnRNPA1 controls neointima formation through regulating stem/progenitor cell differentiation and/or smooth muscle cell phenotypic switching. 5.hnRNPA1 expression in human normal and diseased arteries.

血管壁干/祖细胞向平滑肌细胞（SMCs）分化及成熟SMCs的表型转化均参与血管损伤后修复及病理性重塑过程。如果能找到一种分子，即能促进血管壁干细胞分化为收缩型的SMCs，又能维持成熟SMCs的收缩表型、抑制其发生表型转化，有可能成为有效防治动脉粥样硬化、再狭窄等血管疾病的理想方法。我们已经发现hnRNPA1能促进胚胎干细胞分化为SMCs，近期预实验结果显示hnRNPA1还能调控SMCs表型转化。本项目拟研究：1. hnRNPA1在血管壁干/祖细胞向SMCs分化中的作用及其对分化来的SMCs功能的影响；2. hnRNPA1对成熟SMCs表型转化后增殖、迁移功能的影响及其分子机制；3. hnRNPA1对小鼠颈动脉导丝损伤后内膜新生的作用；4. hnRNPA1对血管损伤后内膜新生的影响是否通过调控干/祖细胞分化和/或SMCs表型转化来实现；5. 人体病变血管及正常血管中hnRNPA1的表达差异。

目的：hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1)在不同疾病过程中起到不同作用。但是关于hnRNPA1调控血管平滑肌细胞功能及内膜新生仍未见相关报道。本研究的目标是探索hnRNPA1在血管平滑肌细胞功能、导丝损伤所导致的血管重构以及人动脉粥样硬化斑块形成中的作用，并揭示其潜在的分子机制。 .方法和结果：hnRNPA1在平滑肌细胞表型转化和导丝损伤所导致内膜新生过程中表达变化一致。功能研究显示，hnRNPA1能调节血管平滑肌细胞的特异性基因表达以及增殖和迁移功能。hnRNPA1的平滑肌细胞的调控作用主要通过上调microRNA-124 (miR-124) 和结合IQGAP1 (IQ motif containing GTPase activating protein 1)基因的AU富集区两种方式实现。进一步研究证实，IQGAP1是miR-124的下游靶基因。更为重要的是，过表达hnRNPA1能显著抑制血管平滑肌细胞增殖，进而抑制导丝损伤所导致的颈动脉内膜异常增生。最后在临床病人动脉粥样硬化血管中我们发现，相比正常人的健康血管，病变血管中hnRNPA1和miR-124表达明显降低而IQGAP1表达显著上升。.结论：本研究成功揭示了hnRNPA1在血管平滑肌细胞功能和血管损伤后内膜新生中的作用，hnRNPA1/miR-124/IQGAP1调控轴是心血管疾病防治的新型调控靶点。