Lucas A, Liu L, Macen J, Nash P, Dai E, Stewart M, Graham K, Etches W, Boshkov L, Nation P N, Humen D, Hobman M L, McFadden G
Department of Medicine, University of Alberta, Edmonton, Canada.
Circulation. 1996 Dec 1;94(11):2890-900. doi: 10.1161/01.cir.94.11.2890.
Recurrent atherosclerotic plaque growth, restenosis, is a significant clinical problem after interventional procedures. Initiation of restenosis involves activation of inflammatory and thrombotic cascades, which are regulated by serine proteinase enzymes and inhibitors. We have investigated the use of a viral serine proteinase inhibitor, SERP-1, to reduce plaque development after primary balloon angioplasty. This is the first experimental report of the use of a viral anti-inflammatory protein for the prevention of atherosclerosis.
Seventy-four cholesterol-fed rabbits were treated with either local or systemic infusions of SERP-1 protein (or control solutions) after balloon-mediated injury. Sites of SERP-1 infusion in rabbits had dramatically reduced plaque compared with control infusions at the 4-week follow-up. At low-dose infusions (30 to 300 pg), only the primary infusion site had a demonstrable decrease in plaque, whereas at higher-dose infusions (> 3000 pg), a generalized reduction in plaque development was detected. An associated decrease in mononuclear cell infiltration of the arterial wall was detected after SERP-1 infusion within the first 24 hours. Infusion of an active-site mutant of SERP-1 (P1-P1', ala-ala) lacking serine proteinase inhibitory activity failed to prevent plaque growth.
Purified SERP-1, a virus-encoded secreted glycoprotein, reduces plaque growth after primary balloon-mediated injury. Plaque development is decreased by inhibition of serine proteinase activity and is associated with a focal reduction in macrophage infiltration immediately after injury. Investigation of serine proteinase inhibitors may provide new insight into the regulation of arterial responses to injury.
复发性动脉粥样硬化斑块生长，即再狭窄，是介入手术后一个重要的临床问题。再狭窄的起始涉及炎症和血栓形成级联反应的激活，这些反应由丝氨酸蛋白酶及其抑制剂调节。我们研究了使用病毒丝氨酸蛋白酶抑制剂SERP-1来减少初次球囊血管成形术后的斑块形成。这是关于使用病毒抗炎蛋白预防动脉粥样硬化的首篇实验报告。
74只喂食胆固醇的兔子在球囊介导损伤后接受局部或全身注射SERP-1蛋白（或对照溶液）。在4周随访时，与对照注射相比，兔子中SERP-1注射部位的斑块显著减少。在低剂量注射（30至300皮克）时，只有初次注射部位的斑块有明显减少，而在高剂量注射（>3000皮克）时，检测到斑块形成普遍减少。在注射SERP-1后的头24小时内，检测到动脉壁单核细胞浸润相关减少。注射缺乏丝氨酸蛋白酶抑制活性的SERP-1活性位点突变体（P1-P1'，丙氨酸-丙氨酸）未能阻止斑块生长。
纯化的SERP-1，一种病毒编码的分泌糖蛋白，可减少初次球囊介导损伤后的斑块生长。通过抑制丝氨酸蛋白酶活性可减少斑块形成，且与损伤后立即出现的巨噬细胞浸润局部减少有关。对丝氨酸蛋白酶抑制剂的研究可能为动脉损伤反应的调节提供新的见解。
