Gertz S D, Fallon J T, Gallo R, Taubman M B, Banai S, Barry W L, Gimple L W, Nemerson Y, Thiruvikraman S, Naidu S S, Chesebro J H, Fuster V, Sarembock I J, Badimon J J
Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Circulation. 1998 Aug 11;98(6):580-7. doi: 10.1161/01.cir.98.6.580.
Tissue factor (TF) is a transmembrane glycoprotein that, after binding to factor VII/VIIa, initiates the extrinsic coagulation pathway, resulting in thrombin generation and its sequelae. Thrombin has been shown to induce TF mRNA in endothelium, monocytes, and smooth muscle cells, further perpetuating the thrombogenic cycle. This study was designed to determine the effect of specific inhibition of thrombin by recombinant hirudin (r-hirudin) on TF distribution after balloon angioplasty in the cholesterol-fed rabbit femoral artery and porcine coronary artery models.
Thirty-five femoral arteries from 32 cholesterol-fed New Zealand White rabbits and 84 coronary arteries from 55 Yorkshire-Albino swine were studied by use of a recently developed in situ method of TF localization based on digoxigenin labeling of recombinant factor VIIa (Dig-VIIa), with correlative studies of TF immunoreactivity by use of anti-rabbit (AP-1) or anti-human (sTF) antibodies. At sites of balloon angioplasty in rabbit femoral or pig coronary arteries (double or single injury), TF-antibody and Dig-VIIa staining were noted in association with endothelial cells, smooth muscle cells, and foam cells and within the fibrous tissue matrix primarily of the adventitia and neointima. Staining was significantly greater after balloon angioplasty than in vessels that had not undergone angioplasty but was similar after single and double balloon injury. Animals treated with r-hirudin (rabbits, 1 mg/kg bolus plus 2-hour infusion; pigs, 1 mg/kg bolus plus 0.7 mg x kg(-1) x d(-1) infusion for 14 days with implantable pump) had diminished TF-antibody and Dig-VIIa staining 28 days after balloon angioplasty compared with controls (bolus heparin only). This effect was more prominent on the neointima and was more striking in the porcine than the rabbit model.
TF expression, persistent 1 month after balloon angioplasty in rabbit femoral arteries and porcine coronary arteries, is attenuated by specific thrombin inhibition with hirudin. These results suggest that thrombin inhibition, in addition to its effect on acute thrombus formation and its effect on luminal narrowing by plaque in experimental animals, may result in a prolonged reduction in thrombogenicity of the restenotic plaque through this effect on TF expression.
组织因子（TF）是一种跨膜糖蛋白，与因子VII/VIIa结合后启动外源性凝血途径，导致凝血酶生成及其后续反应。已证实凝血酶可诱导内皮细胞、单核细胞和平滑肌细胞中的TF mRNA表达，进一步使血栓形成循环持续存在。本研究旨在确定在胆固醇喂养的兔股动脉和猪冠状动脉模型中，重组水蛭素（r - 水蛭素）特异性抑制凝血酶对球囊血管成形术后TF分布的影响。
使用基于重组因子VIIa地高辛标记（Dig - VIIa）的最新原位TF定位方法，对32只胆固醇喂养的新西兰白兔的35条股动脉和55只约克郡 - 白化猪的84条冠状动脉进行研究，并使用抗兔（AP - 1）或抗人（sTF）抗体对TF免疫反应性进行相关研究。在兔股动脉或猪冠状动脉的球囊血管成形术部位（单次或双重损伤），在内皮细胞、平滑肌细胞和泡沫细胞以及主要在外膜和新生内膜的纤维组织基质内，可观察到TF抗体和Dig - VIIa染色。球囊血管成形术后的染色明显高于未进行血管成形术的血管，但单次和双重球囊损伤后的染色相似。用r - 水蛭素治疗的动物（兔，静脉注射1 mg/kg加2小时输注；猪，静脉注射1 mg/kg加0.7 mg·kg⁻¹·d⁻¹输注14天，使用植入式泵）在球囊血管成形术后28天，与对照组（仅静脉注射肝素）相比，TF抗体和Dig - VIIa染色减少。这种作用在新生内膜上更明显，在猪模型中比兔模型更显著。
在兔股动脉和猪冠状动脉中，球囊血管成形术后1个月持续存在的TF表达，通过水蛭素特异性抑制凝血酶而减弱。这些结果表明，凝血酶抑制除了对实验动物急性血栓形成和斑块导致的管腔狭窄有作用外，还可能通过对TF表达的这种作用，使再狭窄斑块的血栓形成性长期降低。
