Tissue factor pathway inhibitor inhibits endothelial cell proliferation via association with the very low density lipoprotein receptor
Tissue factor pathway inhibitor inhibits endothelial cell proliferation via association with the very low density lipoprotein receptor
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DOI：
10.1074/jbc.m010395200
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发表时间：
2001-04-13
影响因子：
4.8
通讯作者：
Strickland, DK
中科院分区：
文献类型：
--
作者：
Hembrough, TA;Ruiz, JF;Strickland, DK
组织因子途径抑制物（TFPI）含有三个Kunitz型蛋白酶抑制剂结构域，是一种有效的组织因子介导的凝血抑制剂。在这里，我们报告TFPI抑制碱性成纤维细胞生长因子刺激的内皮细胞的增殖。TFPI的截短形式，只含有前两个Kunitz型蛋白酶抑制剂结构域，具有非常小的抗增殖活性，这表明TFPI的羧基末端区域负责这种活性。结合研究表明，全长TFPI，但不是截短的TFPI分子，是由极低密度脂蛋白受体（VLDL受体），这表明该受体是一种新的高亲和力的内皮细胞受体TFPI识别。TFPI对内皮细胞的抗增殖活性受到受体相关蛋白（一种已知的VLDL受体结合配体的拮抗剂）和抗VLDL受体抗体的抑制。这些结果证实TFPI的抗增殖活性是由VLDL受体介导的，并表明该受体-配体系统可能是开发新的抗血管生成和抗肿瘤药物的有用靶点。
Tissue factor pathway inhibitor (TFPI) contains three Kunitz-type proteinase inhibitor domains and is a potent inhibitor of tissue factor-mediated coagulation. Here, we report that TFPI inhibits the proliferation of basic fibroblast growth factor-stimulated endothelial cells. A truncated form of TFPI, containing only the first two Kunitz-type proteinase inhibitor domains, has very little antiproliferative activity, suggesting that the carboxyl-terminal region of TFPI is responsible for this activity. Binding studies revealed that full-length TFPI, but not the truncated TFPI molecule, is recognized by the very low density lipoprotein receptor (VLDL receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for TFPI. The antiproliferative activity of TFPI on endothelial cells is inhibited by the receptor-associated protein, a known antagonist of ligand binding by the VLDL receptor, and by anti-VLDL receptor antibodies. These results confirm that the antiproliferative activity of TFPI is mediated by the VLDL receptor and suggest that this receptor-ligand system may be a useful target for the development of new antiangiogenic and antitumor agents.