miR-17~92 cluster 调控VSMC表型转化在移植静脉术后再狭窄中的作用及机制研究

血管平滑肌细胞(VSMC)表型转化、过度增殖迁移所致的内膜增生是冠状动脉旁路移植(CABG)术后移植静脉再狭窄发生的主要病理机制。microRNA(miR)是调控VSMC生物学功能的重要因子，我们前期实验发现miR-17~92 cluster在移植静脉再狭窄动物模型和VSMC表型转化模型中均高表达，且伴随Smad4基因的低表达，进一步理论预测发现miR-17~92 与Smad4 mRNA的3'UTR存在关键结合位点。本课题拟通过细胞和动物实验明确miR-17~92 cluster 是否参与VSMC表型转化、增殖和迁移的调控；通过荧光素酶报告实验明确Smad4是否是miRNA-17~92 cluster调控的直接功能性靶基因；靶向抑制miR-17~92 cluster是否可以有效缓解移植静脉术后内膜增生再狭窄的形成。本课题将为CABG术后移植静脉再狭窄的发生发展机制和防治研究提供新的切入点。

Vein grafts failure remains an important and unresolved problem of coronary artery bypass grafting (CABG) surgery. The main pathogenesis of vein graft restenosis is neointimal hyperplasia associated with vascular smooth muscle cell (VSMC) dedifferentiation, migration and proliferation. Phenotypic modulation of VSMC by miRs plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. In the preliminary study, we have identified abundant expression of miR-17~92 cluster in vein graft restenosis rat model and VSMC dedifferentiation model. Smad4 as a potential target gene of miR-17~92 cluster according to its mRNA 3’-UTR complementary to miR-17~92 cluster by searching for Targetscan database. Therefore, the objective of the study was to evaluate the role, if any, of miR-17~92 cluster in VSMC phenotypic switch in vitro and in response to neointimal hyperplasia lesion formation after vein graft in vivo. Furthermore, to verify that Smad4 as a downstream target gene of miR-17~92 cluster by luciferase activity assay in vitro. The findings of this study may represent promising therapeutic targets in vein graft restenosis after coronary artery bypass grafting surgery.