A Small Molecule Inhibitor to Plasminogen Activator Inhibitor 1 Inhibits Macrophage Migration
A Small Molecule Inhibitor to Plasminogen Activator Inhibitor 1 Inhibits Macrophage Migration
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DOI：
10.1161/atvbaha.113.301224
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发表时间：
2013-05-01
影响因子：
8.7
通讯作者：
Miyata, Toshio
中科院分区：
文献类型：
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作者：
Ichimura, Atsuhiko;Matsumoto, Sachiko;Miyata, Toshio
巨噬细胞（M phi）的迁移依赖于M phi表面成分与细胞外基质之间的粘附/分离，以及许多炎性疾病的贡献。纤溶酶原激活物抑制剂（派）-1是一种丝氨酸蛋白酶抑制剂，通过一种不同于经典的纤溶酶纤溶过程的调节作用影响M phi的运动。我们在这里依赖于一个小分子派-1抑制剂（TM 5275），以探讨派-1在M phi迁移中的作用，在肾injuries.Approach和Results-M phi迁移抑制TM 5275在体外和体内。在T细胞缺陷的裸鼠中也减少了，但在派-1缺陷的小鼠中没有。M.迁移依赖于派-1与低密度脂蛋白受体相关蛋白的相互作用，这种相互作用被TM 5275阻止，但不依赖于与玻连蛋白、尿激酶型纤溶酶原激活剂或组织型纤溶酶原激活剂的相互作用。喂食大鼠抗Thy-1诱导的肾炎，TM 5275显着降低M phi积累和改善肾injuries. Conclusions的进展，这些研究结果表明，小分子派-1抑制剂代表一类新的抗炎药靶向M phi迁移抑制派-1与低密度脂蛋白受体相关蛋白的相互作用。（Arterioscler Thromb Vasc Biol.2013; 33：935-942.）
Objective-Macrophage (M phi) migration rests on the adhesion/detachment between M phi surface components and extracellular matrixes, and the contribution of numerous inflammatory disorders. Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, influences M phi motility through an action distinct from its classical modulation of the plasmin-based fibrinolytic process. We rely here on a small molecule PAI-1 inhibitor (TM5275) to investigate the role of PAI-1 in M phi migration in the pathogenesis of renal injury.Approach and Results-M phi migration was inhibited both in vitro and in vivo by TM5275. It was also reduced in T-cell-deficient nude mice, but not in PAI-1-deficient mice. M. migration hinged on the interaction of PAI-1 with low-density lipoprotein receptor-related protein, an interaction prevented by TM5275, but not with vitronectin, urokinase-type plasminogen activator, or tissue-type plasminogen activator. Fed to rats with anti-Thy-1-induced nephritis, TM5275 significantly decreased M phi accumulation and ameliorated the progression of renal injury.Conclusions-These findings suggest that a small molecule PAI-1 inhibitor represents a novel class of anti-inflammatory agents targeting M phi migration by the inhibition of the interaction of PAI-1 with low-density lipoprotein receptor-related protein. (Arterioscler Thromb Vasc Biol. 2013; 33: 935-942.)