Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries
Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries
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DOI：
10.1161/01.cir.98.6.580
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发表时间：
1998-08-11
期刊：
影响因子：
37.8
通讯作者：
Badimon, JJ
中科院分区：
文献类型：
--
作者：
Gertz, SD;Fallon, JT;Badimon, JJ
背景-组织因子(Tf)是一种跨膜糖蛋白，与凝血因子VII/VIIa结合后，启动外源性凝血途径，导致凝血酶的产生及其后遗症。凝血酶已被证明可诱导血管内皮细胞、单核细胞和平滑肌细胞中的转铁蛋白mRNA，进一步延长血栓形成周期。本研究旨在探讨重组水飞蓟素(r-Hirudin)对兔股动脉和猪冠状动脉球囊成形术后凝血酶的特异性抑制作用。方法与结果：采用地高辛标记重组因子VIIa的原位组织化学方法，结合抗兔抗体(AP-1)和抗人抗体(STF)，对32只高脂饮食的新西兰大白兔的35条股动脉和55条约克夏白化猪的84条冠状动脉进行了组织因子的原位定位。在兔股动脉或猪冠状动脉球囊成形术(双伤或单伤)部位，TF抗体和Dig-VIIa染色主要见于血管内皮细胞、平滑肌细胞和泡沫细胞以及纤维组织基质内，主要位于外膜和新生内膜。球囊血管成形术后的染色显着高于未接受血管成形术的血管，但在单球囊和双球囊损伤后相似。与对照组(单用肝素)相比，球囊血管成形术后28d，重组水飞蓟素治疗组(兔，1 mg/kg静脉推注+2小时输注；猪，1 mg/kg推注+0.7 mg·kg(-1).d(-1)静脉滴注14天)，TF抗体和Dig-VIIa染色减弱，这种作用在新生内膜上更明显，在猪身上比兔模型更明显。结论球囊血管成形术后1个月，特异性凝血酶抑制兔股动脉和猪冠状动脉组织中TF的表达。这些结果表明，凝血酶抑制除了对动物急性血栓形成和斑块所致管腔狭窄的影响外，还可能通过对TF表达的影响而导致再狭窄斑块的血栓形成能力的长期降低。
Background-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.Methods and Results-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.kg(-1).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.Conclusions-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.