Ji W R, Barrientos L G, Llinás M, Gray H, Villarreal X, DeFord M E, Castellino F J, Kramer R A, Trail P A
Department of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceuticals, Inc., Provinceline & Route 206, Princeton, New Jersey, 08543, USA.
Biochem Biophys Res Commun. 1998 Jun 18;247(2):414-9. doi: 10.1006/bbrc.1998.8825.
Angiogenesis is a multi-step process that includes endothelial cell proliferation, migration, basement membrane degradation, and new lumen organization. Angiostatin, an internal fragment of plasminogen comprising the first four triple disulfide-linked kringle structures, is one of the most potent endogenous angiogenesis inhibitors described to date. The kringle 5 domain of plasminogen, which shares high sequence homology with the four kringles of angiostatin, was previously shown to antagonize endothelial cell growth. We now describe that the recombinant kringle 5 of human plasminogen inhibits endothelial cell migration with an IC50 (concentration for half maximal inhibition) of approximately 500 nM. We demonstrate that the lysine-binding sites of kringle 5 may not be involved in its anti-migratory activities. The anti-migratory activity of kringle 5 is similar to that of angiostatin. Kringle 5 also shows selective inhibition on endothelial cells as opposed to other cell types. Relative to its native form, reduced kringle 5 displays a significant increase in anti-migratory activity, implying that the kringle conformation may shield kringle 5 from effectively interacting with endothelial cells. This report thus constitutes the first demonstration that kringle 5 of plasminogen is a selective inhibitor for endothelial cell migration.
血管生成是一个多步骤过程，包括内皮细胞增殖、迁移、基底膜降解和新管腔形成。血管抑素是纤溶酶原的一个内部片段，由前四个三重二硫键连接的kringle结构组成，是迄今为止描述的最有效的内源性血管生成抑制剂之一。纤溶酶原的kringle 5结构域与血管抑素的四个kringle具有高度序列同源性，先前已证明其可拮抗内皮细胞生长。我们现在描述，重组人纤溶酶原kringle 5以约500 nM的IC50（半数最大抑制浓度）抑制内皮细胞迁移。我们证明kringle 5的赖氨酸结合位点可能不参与其抗迁移活性。kringle 5的抗迁移活性与血管抑素相似。与其他细胞类型相比，kringle 5对内皮细胞也表现出选择性抑制。相对于其天然形式，还原型kringle 5的抗迁移活性显著增加，这意味着kringle构象可能会阻碍kringle 5与内皮细胞有效相互作用。因此，本报告首次证明纤溶酶原kringle 5是内皮细胞迁移的选择性抑制剂。
