Larsson H, Akerud P, Nordling K, Raub-Segall E, Claesson-Welsh L, Björk I
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
J Biol Chem. 2001 Apr 13;276(15):11996-2002. doi: 10.1074/jbc.M010170200. Epub 2001 Jan 12.
Latent antithrombin, an inactive antithrombin form with low heparin affinity, has previously been shown to efficiently inhibit angiogenesis and tumor growth. We now show that heat treatment similar to that used for preparation of latent antithrombin also transforms antithrombin to another form, which we denote prelatent, with potent anti-angiogenic and anti-tumor activity but with retained proteinase- and heparin-binding properties. The ability of prelatent antithrombin to inhibit angiogenesis is presumably due to a limited conformational change, which may partially resemble that in latent antithrombin. Such a change is evidenced by a different cleavage pattern of prelatent than of native antithrombin by nontarget proteinases. Prelatent antithrombin exerts its anti-angiogenic effect by a similar mechanism as latent antithrombin, i.e. by inhibiting focal adhesion formation and focal adhesion kinase activity, thereby leading to decreased proliferation of endothelial cells. The proteinase inhibitory fractions in commercial antithrombin preparations, which have been heat treated during production, also have anti-angiogenic activity, comparable with that of the prelatent antithrombin form.
潜在抗凝血酶是一种与肝素亲和力低的无活性抗凝血酶形式，先前已被证明能有效抑制血管生成和肿瘤生长。我们现在表明，类似于用于制备潜在抗凝血酶的热处理也能将抗凝血酶转化为另一种形式，我们将其称为前潜在抗凝血酶，它具有强大的抗血管生成和抗肿瘤活性，但保留了蛋白酶和肝素结合特性。前潜在抗凝血酶抑制血管生成的能力可能归因于有限的构象变化，这可能部分类似于潜在抗凝血酶中的构象变化。非靶标蛋白酶对前潜在抗凝血酶的切割模式与天然抗凝血酶不同，这证明了这种变化。前潜在抗凝血酶通过与潜在抗凝血酶类似的机制发挥其抗血管生成作用，即通过抑制粘着斑形成和粘着斑激酶活性，从而导致内皮细胞增殖减少。商业抗凝血酶制剂中经过生产过程热处理的蛋白酶抑制部分也具有抗血管生成活性，与前潜在抗凝血酶形式相当。
