EFFECT OF THROMBIN INHIBITION BY HIRUDIN ON ANGIOPLASTY

尽管近30万例经皮腔内冠状动脉成形术 手术，再狭窄并发症约三分之一的情况下， 6个月 导致再狭窄的机制和适当的 再狭窄的治疗方法仍然是未知的。 再狭窄是 这被认为是富含血小板的血栓 血管活性因子和促有丝分裂因子的形成、释放，以及迁移和 扩张血管内膜层平滑肌细胞增生 动脉 最近的研究表明，凝血酶的潜在重要作用 在损伤后的血管愈合中，并且可能导致再狭窄。 与这一假设相一致，我们最近证明了 重组水蛭素（r-水蛭素），一种凝血酶抑制剂， 限制球囊血管成形术后的再狭窄。 本项目的总体目标是通过以下方式确定机制： 凝血酶可能促进球囊扩张后的新生内膜增殖 血管成形术和如何r-水蛭素，一种有效的和特异性的抑制剂， 凝血酶导致较低的再狭窄率。 目标1将决定 球囊扩张后观察到的新生内膜增生减少是否 使用r-水蛭素的血管成形术与其已知的有效抑制相关 体内附壁血栓形成。 目标2将确定是否r-水蛭素- 诱导的新生内膜增殖的减少是由于抑制了 平滑肌细胞迁移和/或增殖。 目标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 用于确定凝血酶是否作为直接促分裂原， 增强了其他已知促分裂剂的作用。 该机制通过 将确定哪种R-水蛭素阻断这些促有丝分裂作用。 目的 4将使用短期的整个器官培养系统来调查 平滑肌细胞的生长调节在Aim 3中确定， 这些条件更能代表体内条件。 采取 总之，这些研究将提供重要的新见解， 凝血酶在球囊血管成形术后血管愈合中的作用 应确定r-水蛭素限制再狭窄的机制。 这项工作在临床上可能会产生相当大的影响， 提高血管成形术的有效性，降低发病率， 限制了总成本。

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.