ERRα信号通路在PCI术后再狭窄中的作用和机制研究

Inflammation, proliferation and migration of smooth muscle cells, as well as extracellular matrix accumulation are involved in the pathological changes of post-angioplasty restenosis (RS). Biological responses of vascular smooth muscle cells (VSMCs) are believed to be the main mechanisms accounting for restenosis after percutaneous transluminal coronary intervention (PCI). As an independent risk factor for poor prognosis, estrogen-related receptor (ERRα) promotes migration and proliferation of multiple types of cancer cells including breast cancer, colon cancer and prostate cancer. Our previous study has suggested that proinflammatory factor TNF-α induces nuclear translocation and translation of ERRα, and also upregulates its expression in VSMCs. Furthermore, transactivation of ERRα enhances the migration of VSMCs. These results indicate that ERRαpromote post-angioplasty restenosis through inducing inflammatory responses, proliferation and migration of VSMCs and secretion of extracellular matrix. For the project, ERRα is taken as the entry point to study the mechanism of restenosis after PCI. Biological responses of VSMCs and pathways involved in ERRα-mediated activation including VEGF, osteopontin and MMPs will be investigated and verified. We believe that the results of the project will further clarify the mechanism of post-angioplasty restenosis and reveal the feasibility of ERRα as the target of prevention and treatment for restenosis after PCI.

血管损伤再狭窄的基本病变包括炎症反应、平滑肌细胞增生、迁移及细胞外基质的积聚。血管平滑肌细胞（VSMC）的生物学应答被认为是PCI术后再狭窄的主要发生机制。ERRα可促进乳腺癌、结肠癌及前列腺癌等肿瘤的迁移与增殖，是临床预后不良的独立风险因子。我们的前期工作表明，炎症因子可刺激VSMC内ERRα表达上调，诱导ERRα核转位及转录活化。并且，ERRα活化使VSMC迁移显著增加。这些结果提示：ERRα可能通过诱导炎症反应、增强VSMC迁移及增殖、增加细胞外基质分泌等一系列途径，促进血管损伤后再狭窄。本项目拟以ERRα作为研究PCI术后再狭窄发生机制的切入点，考察VSMC的生物学应答效应，寻找并验证血管受损后ERRα对VEGF、osteopontin及MMPs等相关信号通路的调控途径。研究结果将进一步阐明血管成形术后再狭窄的机制，揭示ERRα作为防治PCI术后再狭窄靶点的可行性。

血管损伤再狭窄的基本病变包括炎症反应、平滑肌细胞增生、迁移及细胞外基质的积聚。血管平滑肌细胞（VSMC）的生物学应答被认为是PCI 术后再狭窄的主要发生机制。ERRα可促进乳腺癌、结肠癌及前列腺癌等肿瘤的迁移与增殖，是临床预后不良的独立风险因子。本课题研究结果表明，ERRα反向激动剂（或ERRα shRNA）抑制了VSMC的增殖及表型转换；下调ERRα蛋白显著阻滞VSMC细胞周期，抑制细胞周期蛋白的转录及Rb的磷酸化；Transwell实验表明ERRα调控VSMC的迁移。深入的机制研究证实，ERRα介导的VEGF/OPN/MMPs、RhoA/p27Kip1 及 β-Catenin/Wnt4 信号通路，调节了血管平滑肌细胞迁移及增殖，促进血管损伤后VSMC生物学应答。在大鼠球囊损伤模型中，发现ERRα 特异性反向激动剂对球囊损伤所致新生内膜有极为显著的抑制作用，作用机制可能涉及调控血管组织中p27Kip1及Wnt4的蛋白表达。本课题研究结果证实ERRα可能作为防治PCI 术后再狭窄的治疗靶点。