Lucas A, Dai E, Liu L, Guan H, Nash P, McFadden G, Miller L
Vascular Biology Group, John P. Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
J Heart Lung Transplant. 2000 Nov;19(11):1029-38. doi: 10.1016/s1053-2498(00)00190-x.
Surgical and ischemic injury to the artery wall initiates vascular wound-healing responses that stimulate atherosclerotic plaque growth. The plasminogen activators have cellular chemotactic, adhesion, and proteolytic activity. Serp-1 is a secreted myxoma virus glycoprotein serpin that binds and inhibits plasminogen activators. We have examined the effects of Serp-1 on plaque growth and inflammatory cell invasion in animal models after balloon injury and after aortic allograft transplant.
We used histologic analysis to assess 4 animal models of angioplasty-mediated injury and 2 models of aortic allograft transplant for intimal hyperplasia and cellular invasion. We assessed plasminogen activator (uPA and tPA) and inhibitor (PAI-1) expression in rat iliofemoral arteries after balloon injury using Western blot, enzyme activity, and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).
Plaque growth after balloon injury decreased after Serp-1 treatment in all balloon-injury models tested. Transplant vasculopathy also significantly decreased in 2 rat models of aortic allograft transplant. Infusion of a Serp-1 active site mutant, that lacked plasminogen activator inhibiting activity, did not inhibit plaque growth. Quantitative RT-PCR detected increased transcription of PAI-1 mRNA. Increased PAI-1 protein and enzyme-inhibitory activity was also detected in Serp-1-treated arteries by activity assay and Western blot.
Thrombolytic serpins are central regulatory agents in vascular wound-healing responses. Investigation of the inhibitory mechanisms of viral serpins may provide new insights into atherogenesis.
动脉壁的手术损伤和缺血性损伤会引发血管愈合反应，刺激动脉粥样硬化斑块生长。纤溶酶原激活剂具有细胞趋化、黏附和蛋白水解活性。Serp-1是一种分泌型黏液瘤病毒糖蛋白丝氨酸蛋白酶抑制剂，可结合并抑制纤溶酶原激活剂。我们研究了Serp-1对球囊损伤后及主动脉同种异体移植后动物模型中斑块生长和炎症细胞浸润的影响。
我们使用组织学分析评估4种血管成形术介导损伤的动物模型和2种主动脉同种异体移植模型的内膜增生和细胞浸润情况。我们使用蛋白质印迹法、酶活性测定和定量逆转录聚合酶链反应（RT-PCR）评估球囊损伤后大鼠髂股动脉中纤溶酶原激活剂（尿激酶型纤溶酶原激活剂和组织型纤溶酶原激活剂）及抑制剂（纤溶酶原激活剂抑制剂-1）的表达。
在所有测试的球囊损伤模型中，Serp-1治疗后球囊损伤后的斑块生长减少。在2种大鼠主动脉同种异体移植模型中，移植血管病变也显著减少。注入缺乏纤溶酶原激活剂抑制活性的Serp-1活性位点突变体并不能抑制斑块生长。定量RT-PCR检测到纤溶酶原激活剂抑制剂-1 mRNA转录增加。通过活性测定和蛋白质印迹法在Serp-1处理的动脉中也检测到纤溶酶原激活剂抑制剂-1蛋白增加及酶抑制活性增强。
溶栓性丝氨酸蛋白酶抑制剂是血管愈合反应中的核心调节因子。对病毒丝氨酸蛋白酶抑制剂抑制机制的研究可能为动脉粥样硬化的发病机制提供新的见解。
