Han X, Girard T J, Baum P, Abendschein D R, Broze G J
Division of Hematology/Oncology, Barnes-Jewish Hospital at Washington University Medical Center, St. Louis, MO 63110, USA.
Arterioscler Thromb Vasc Biol. 1999 Oct;19(10):2563-7. doi: 10.1161/01.atv.19.10.2563.
The intimal thickening that follows vascular injury is inhibited by periprocedural tissue factor pathway inhibitor (TFPI) treatment in animal models. TFPI is a multivalent Kunitz-type protease inhibitor that inhibits factor Xa via its second Kunitz domain and the factor VIIa/tissue factor (TF) complex via its first Kunitz domain. The basic C-terminus of TFPI is required for the binding of TFPI to cell surfaces and cell-bound TFPI mediates the internalization and degradation of factor X and the down regulation of surface factor VIIa/TF activity. The C-terminus of TFPI is also required for its reported direct inhibition of smooth muscle cell proliferation in vitro. To examine the structural requirements for the inhibition of neointimal formation by TFPI, several TFPI-related proteins were tested in the rat carotid angioplasty model: 1) XK(1), a hybrid protein containing the N-terminal portion of factor X and the first Kunitz domain of TFPI that directly inhibits factor VIIa/TF; 2) TFPI(WT), the full-length TFPI molecule that inhibits factor Xa and factor VIIa/TF and binds cell surfaces; 3) TFPI(K36I), an altered form of TFPI that inhibits factor Xa, but not factor VIIa/TF, and binds cell surfaces; 4) TFPI(13-161), a truncated form of TFPI that inhibits factor VIIa/TF but interacts with factor Xa poorly and does not bind to cell surfaces. Seven day infusions of XK(1), TFPI(WT), and high levels of TFPI(K36I) begun the day before balloon-induced vascular injury produced a significant reduction in the intimal hyperplasia measured 28 days after angioplasty. The infusion of high concentrations of TFPI(13-161) was ineffective in this model. These in vivo results directly mirror the ability of each TFPI-related protein to inhibit tissue thromboplastin-induced coagulation in rat plasma: XK(1) approximately TFPI(WT)>TFPI(K36I)>>TFPI(13-161). The studies confirm the important role of TF-mediated coagulation in the smooth muscle proliferation and neointimal thickening that follows vascular injury and suggest that the anticoagulant effect alone of TFPI and TFPI-related proteins is sufficient to explain their therapeutic action.
在动物模型中，血管损伤后发生的内膜增厚可被围手术期组织因子途径抑制剂（TFPI）治疗所抑制。TFPI是一种多价的Kunitz型蛋白酶抑制剂，它通过其第二个Kunitz结构域抑制因子Xa，并通过其第一个Kunitz结构域抑制因子VIIa/组织因子（TF）复合物。TFPI的碱性C末端是TFPI与细胞表面结合所必需的，而细胞结合型TFPI介导因子X的内化和降解以及表面因子VIIa/TF活性的下调。TFPI的C末端对于其在体外直接抑制平滑肌细胞增殖的作用也是必需的。为了研究TFPI抑制新生内膜形成的结构要求，在大鼠颈动脉血管成形术模型中测试了几种与TFPI相关的蛋白：1）XK(1)，一种杂合蛋白，包含因子X的N末端部分和TFPI的第一个Kunitz结构域，可直接抑制因子VIIa/TF；2）TFPI(WT)，全长TFPI分子，可抑制因子Xa和因子VIIa/TF并结合细胞表面；3）TFPI(K36I)，TFPI的一种变体形式，可抑制因子Xa，但不能抑制因子VIIa/TF，并结合细胞表面；4）TFPI(13 - 161)，TFPI的截短形式，可抑制因子VIIa/TF，但与因子Xa相互作用较差且不结合细胞表面。在球囊诱导的血管损伤前一天开始，连续7天输注XK(1)、TFPI(WT)和高水平的TFPI(K36I)，可使血管成形术后28天测得的内膜增生显著减少。在该模型中，输注高浓度的TFPI(13 - 161)无效。这些体内结果直接反映了每种与TFPI相关的蛋白在大鼠血浆中抑制组织凝血活酶诱导的凝血的能力：XK(1)≈TFPI(WT)>TFPI(K36I)>>TFPI(13 - 161)。这些研究证实了TF介导的凝血在血管损伤后平滑肌增殖和内膜增厚中的重要作用，并表明TFPI和与TFPI相关的蛋白仅靠抗凝作用就足以解释它们的治疗作用。
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