Dai Erbin, Guan Haiyan, Liu Liying, Little Stephen, McFadden Grant, Vaziri Sepideh, Cao Henian, Ivanova Iordanka A, Bocksch Leila, Lucas Alexandra
Vascular Biology Research Group, John P. Robarts' Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada.
J Biol Chem. 2003 May 16;278(20):18563-72. doi: 10.1074/jbc.M209683200. Epub 2003 Mar 10.
Complex DNA viruses have tapped into cellular serpin responses that act as key regulatory steps in coagulation and inflammatory cascades. Serp-1 is one such viral serpin that effectively protects virus-infected tissues from host inflammatory responses. When given as purified protein, Serp-1 markedly inhibits vascular monocyte invasion and plaque growth in animal models. We have investigated mechanisms of viral serpin inhibition of vascular inflammatory responses. In vascular injury models, Serp-1 altered early cellular plasminogen activator (tissue plasminogen activator), inhibitor (PAI-1), and receptor (urokinase-type plasminogen activator) expression (p < 0.01). Serp-1, but not a reactive center loop mutant, up-regulated PAI-1 serpin expression in human endothelial cells. Treatment of endothelial cells with antibody to urokinase-type plasminogen activator and vitronectin blocked Serp-1-induced changes. Significantly, Serp-1 blocked intimal hyperplasia (p < 0.0001) after aortic allograft transplant (p < 0.0001) in PAI-1-deficient mice. Serp-1 also blocked plaque growth after aortic isograft transplant and after wire-induced injury (p < 0.05) in PAI-1-deficient mice indicating that increase in PAI-1 expression is not required for Serp-1 to block vasculopathy development. Serp-1 did not inhibit plaque growth in uPAR-deficient mice after aortic allograft transplant. We conclude that the poxviral serpin, Serp-1, attenuates vascular inflammatory responses to injury through a pathway mediated by native uPA receptors and vitronectin.
复杂DNA病毒利用了细胞丝氨酸蛋白酶抑制剂反应，这些反应是凝血和炎症级联反应中的关键调节步骤。Serp-1就是这样一种病毒丝氨酸蛋白酶抑制剂，它能有效保护病毒感染的组织免受宿主炎症反应的影响。当以纯化蛋白形式给予时，Serp-1在动物模型中显著抑制血管单核细胞浸润和斑块生长。我们研究了病毒丝氨酸蛋白酶抑制剂抑制血管炎症反应的机制。在血管损伤模型中，Serp-1改变了早期细胞纤溶酶原激活物（组织纤溶酶原激活物）、抑制剂（PAI-1）和受体（尿激酶型纤溶酶原激活物）的表达（p<0.01）。Serp-1而非反应中心环突变体上调了人内皮细胞中PAI-1丝氨酸蛋白酶抑制剂的表达。用抗尿激酶型纤溶酶原激活物和玻连蛋白的抗体处理内皮细胞可阻断Serp-1诱导的变化。重要的是，在PAI-1缺陷小鼠的主动脉同种异体移植后，Serp-1可阻断内膜增生（p<0.0001）（p<0.0001）。在PAI-1缺陷小鼠的主动脉同基因移植后以及钢丝诱导损伤后，Serp-1也可阻断斑块生长（p<0.05），这表明Serp-1阻断血管病变发展并不需要PAI-1表达增加。在主动脉同种异体移植后，Serp-1并未抑制uPAR缺陷小鼠的斑块生长。我们得出结论，痘病毒丝氨酸蛋白酶抑制剂Serp-1通过由天然uPA受体和玻连蛋白介导的途径减轻血管对损伤的炎症反应。
