MicroRNA-24在糖尿病血管重构中的作用及分子机制研究

Vascular remodeling is the common pathological basis of diabetic chronic complications, which is also the leading cause of disability and mortality among patients with diabetes mellitus. Therefore, it is important to choose the appropriate intervention target of vascular remodeling pathway for the prevention of diabetic vascular complications. According to the miRNA expression profile in rat carotid arteries and our preliminary research work, we found that downregulated "miR-24 on vascular smooth muscle specificity" after balloon injury might be one of the key miRNAs involved in vascular remodeling. In the present study, (1) we attempt to observe the influence of miR-24 overexpression or silencing on the phenotype and function of vascular smooth muscle cell induced by high glucose; explore the multiple sites regulatory mechanism of miR-24 targeted HMGB1, PDGF-R, PI3KR1, WNT4, IFNG gene and the down stream signaling pathways; (2) investigate and evaluate the effect of up-regualtion of miR-24 expression on vascular remodeling after balloon injury in carotid arteries of diabetic rats. The successful application of our research program will further elucidate the molecular mechanism of miR-24 on diabetic vascular remodeling, and provide a prospective strategy and target for the treatment of diabetic vascular complications.

血管重构为糖尿病慢性并发症的共同病理基础，是糖尿病患者致残、致死的最主要因素，研究作用于血管重构通路的靶分子对于防治糖尿病血管并发症具有重大意义。本课题组结合大鼠血管组织特异性miRNAs表达谱芯片，选取前期研究证实在大鼠颈动脉球囊损伤模型中显著下调的"血管平滑肌特异性miR-24"为切入点：（1）通过上调或抑制血管平滑肌细胞（VSMC）的miR-24表达，观察miR-24对高糖诱导的VSMC表型和功能的影响，探索其对靶基因HMGB1、PDGF-R、PI3KR1、WNT4、IFNG及相关信号转导通路的"多位点干预机制"；（2）建立糖尿病大鼠颈动脉球囊损伤模型，从整体水平探讨局部上调损伤血管处miR-24表达对血管重构的影响。通过本项目的成功实施，可进一步阐明miR-24在糖尿病血管重构中的作用和分子机制，为临床防治糖尿病血管并发症提供新的实验依据及干预靶点。

血管重构为糖尿病慢性并发症的共同病理基础，是糖尿病患者致残、致死的最主要因素，研究作用于血管重构通路的靶分子对于防治糖尿病血管并发症具有重大意义。本课题组结合大鼠血管组织特异性miRNAs表达谱芯片，选取前期研究证实在大鼠颈动脉球囊损伤模型中显著下调的“血管平滑肌特异性miR-24”为切入点：（1）通过上调血管平滑肌细胞（VSMCs）的miR-24表达，观察miR-24对高糖诱导的VSMC功能的影响，探索其对靶基因HMGB1、PDGF-R、PI3KR1、WNT4、OGT及相关信号转导通路的“多位点干预机制”；（2）建立糖尿病大鼠颈动脉球囊损伤模型，从整体水平探讨局部上调损伤血管处miR-24表达对血管重构的影响。目前已取得的研究结果如下：（1）腺病毒成功转染VSMCs；（2）过表达miR-24显著抑制其靶基因 HMGB1、PDGF-R、PI3KR1、WNT4、OGT基因的表达；（3）过表达miR-24可显著抑制高糖诱导的VSMCs增殖和迁移；（4）过表达miR-24可显著抑制血管内膜增生、炎症反应和胶原沉积；（5）过表达miR-24可通过拮抗氧化应激损伤，促进血管内皮化修复。通过本项目的成功实施，可进一步阐明miR-24在糖尿病血管重构中的作用和分子机制，为临床防治糖尿病血管并发症提供新的实验依据及干预靶点。