Li Xing, Schneider Heather, Peters Andrew, Macaulay Colin, King Elaine, Sun Yunming, Liu Liying, Dai Erbin, Davids Jennifer A, McFadden Grant, Lucas Alexandra
Viron Therapeutics Inc., London, Ontario, Canada.
Open Biochem J. 2008;2:6-15. doi: 10.2174/1874091X00802010006. Epub 2008 Feb 6.
Serine protease inhibitors (serpins) regulate coagulation and inflammation. Heparin, a glycosaminoglycan, is an important cofactor for modulation of the inhibitory function of mammalian serpins. The secreted myxoma viral serpin, Serp-1 exerts profound anti-inflammatory activity in a wide range of animal models. Serp-1 anti-inflammatory and anti-atherogenic activity is dependent upon inhibition of the uPA / uPA receptor thrombolytic complex. We demonstrate here that heparin binds to Serp-1 and enhances Serp-1 inhibition of thrombin, a human pro-thrombotic serine protease, in vitro, altering inhibitory activity to a more predominant anti-thrombotic activity. Heparin also facilitates the simultaneous thrombin-mediated cleavage of Serp-1 and prevents formation of a serpin-typical SDS-resistant complex, implying mutual neutralization of Serp-1 and thrombin. In a cell-based assay, heparin facilitates Serp-1 reversal of cellular activation by stabilizing cellular membrane fluidity in thrombin-activated monocytes. In conclusion, heparin and other GAGs serve as cofactors enhancing Serp-1 regulation of local thrombotic and inflammatory pathways.
丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂家族）调节凝血和炎症反应。肝素作为一种糖胺聚糖，是调节哺乳动物丝氨酸蛋白酶抑制剂家族抑制功能的重要辅助因子。分泌型黏液瘤病毒丝氨酸蛋白酶抑制剂Serp-1在多种动物模型中发挥着显著的抗炎活性。Serp-1的抗炎和抗动脉粥样硬化活性依赖于对尿激酶型纤溶酶原激活物/尿激酶型纤溶酶原激活物受体溶栓复合物的抑制作用。我们在此证明，肝素与Serp-1结合，并在体外增强Serp-1对凝血酶（一种人促血栓形成丝氨酸蛋白酶）的抑制作用，将抑制活性转变为更主要的抗血栓形成活性。肝素还促进凝血酶介导的Serp-1同时裂解，并阻止形成丝氨酸蛋白酶抑制剂典型的抗十二烷基硫酸钠复合物，这意味着Serp-1和凝血酶相互中和。在基于细胞的试验中，肝素通过稳定凝血酶激活的单核细胞中的细胞膜流动性，促进Serp-1逆转细胞活化。总之，肝素和其他糖胺聚糖作为辅助因子，增强Serp-1对局部血栓形成和炎症途径的调节作用。
