EFFECT OF THROMBIN INHIBITION BY HIRUDIN ON ANGIOPLASTY

尽管近30万人接受了经皮冠状动脉腔内成形术 每年的手术，再狭窄会使大约三分之一的病例复杂化 六个月。再狭窄的发生机制(S)及适当 治疗再狭窄的方法仍不清楚。再狭窄是 认为是富含血小板的血栓复杂相互作用的结果 血管活性因子和有丝分裂因子的形成、释放和迁移 扩张后内膜层内膜细胞的增殖 动脉。最近的研究表明凝血酶潜在的重要作用 不利于损伤后血管的愈合，并可能导致再狭窄。 与这一假设一致，我们最近证明了 凝血酶抑制剂重组水飞蓟素的有效性， 在我们的兔模型中限制球囊血管成形术后的再狭窄。 这个项目的总体目标是通过以下方式确定机制(S) 哪种凝血酶可促进球囊扩张后新生内膜的增殖 血管成形术和r-水飞蓟素，一种有效和特异的血管成形术抑制剂 凝血酶，导致较低的再狭窄率。目标一号将决定 观察到的球囊扩张后新生内膜增殖的减少 使用r-水飞蓟素的血管成形术与其已知的有效抑制作用相关 活体内的壁血栓形成。目标2将确定r-水飞蓟素是否- 抑制血管内皮细胞增殖导致新生内膜增殖减少 平滑肌细胞迁移和/或增殖。AIM 3将评估 凝血酶作为有丝分裂原。培养的内皮细胞和平滑肌细胞将 用于确定凝血酶是作为直接有丝分裂原还是作为 增强其他已知的有丝分裂原的作用。机制(S)由 哪些r-水飞蓟素阻断了这些有丝分裂的作用将会被确定。目标 4将使用短期完整的器官培养系统来调查 AIM 3中鉴定的血管内皮细胞生长调控 这些条件更能代表体内的情况。已被占用 总而言之，这些研究将为我们提供对 凝血酶在球囊血管成形术后血管愈合中的作用 应确定r-水飞蓟素抑制再狭窄的机制(S)。 这项工作可能会对临床产生相当大的影响 提高血管成形术的有效性，降低发病率和 限制总成本。

Despite almost 300,000 percutaneous transluminal coronary angioplasty procedures per year, restenosis complicates about one third of cases by 6 months. The mechanism(s) responsible for restenosis and appropriate therapeutic approach(es) to restenosis remain unknown. Restenosis is thought to result from a complex interaction of platelet-rich thrombus formation, release of vasoactive and mitogenic factors, and migration and proliferation of smooth muscle cells in the intimal layer of the dilated artery. Recent studies suggest the potential important role of thrombin in vessel healing following injury, and may contribute to restenosis. Consistent with this hypothesis we have recently demonstrated the effectiveness of recombinant hirudin (r-hirudin), a thrombin inhibitor, in limiting restenosis after balloon angioplasty in our rabbit model. The overall goal of this project is to ascertain the mechanism(s) by which thrombin may promote neointimal proliferation following balloon angioplasty and how r-hirudin, a potent and specific inhibitor of thrombin, results in a lower restenosis rate. Aim 1 will determine whether the observed reduction in neointimal proliferation after balloon angioplasty using r-hirudin correlates with its known potent inhibition of mural thrombosis in-vivo. Aim 2 will ascertain whether the r-hirudin- induced reduction in neointimal proliferation results from inhibition of smooth muscle cell migration and/or proliferation. Aim 3 will evaluate thrombin as a mitogen. Cultured endothelial and smooth muscle cells will be used to determine whether thrombin acts as a direct mitogen or potentiates the effect of other known mitogens. The mechanism(s) by which r-hirudin blocks these mitogenic effects will be determined. Aim 4 will use a short-term whole organ culture system to investigate the growth modulation of smooth muscle cells identified in Aim 3 under conditions that are much more representative of those in-vivo. Taken together, these studies will provide important novel insights into the role of thrombin in vessel healing following balloon angioplasty and should identify the mechanism(s) by which r-hirudin limits restenosis. This work may have considerable impact clinically with respect to enhancing the effectiveness of angioplasty, reducing morbidity and limiting overall cost.