Department of Immunology, Allergy and Infectious Diseases, St. George Hospital, University of New South Wales, Sydney, Australia.
J Autoimmun. 2012 Sep;39(3):121-9. doi: 10.1016/j.jaut.2012.05.005. Epub 2012 Jun 13.
Factor XI (FXI), a disulfide-linked covalent homodimer, circulates in plasma, and upon activation initiates the intrinsic/consolidation phase of coagulation. We present evidence that disulfide bonds in FXI are reduced to free thiols by oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI). We identified that Cys362-Cys482 and Cys118-Cys147 disulfide bonds are reduced by TRX-1. The activation of TRX-1-treated FXI by thrombin, FXIIa or FXIa was significantly increased compared to non-reduced FXI, indicating that the reduced factor is more efficiently activated than the oxidized protein. Using a novel ELISA system, we compared the amount of reduced FXI in antiphospholipid syndrome (APS) thrombosis patients with levels in healthy controls, and found that APS patients have higher levels of reduced FXI. This may have implication for understanding the contribution of FXI to APS thrombosis, and the predisposition to thrombosis in patients with elevated plasma levels of reduced FXI.
因子 XI (FXI) 是一种二硫键连接的共价同二聚体，在血浆中循环，在激活后启动凝血的固有/巩固阶段。我们提供的证据表明，氧化还原酶硫氧还蛋白-1 (TRX-1) 和蛋白二硫键异构酶 (PDI) 将 FXI 中的二硫键还原为游离巯基。我们确定 Cys362-Cys482 和 Cys118-Cys147 二硫键由 TRX-1 还原。与未还原的 FXI 相比，凝血酶、FXIIa 或 FXIa 激活的 TRX-1 处理的 FXI 的激活显著增加，表明还原后的因子比氧化蛋白更有效地激活。使用新型 ELISA 系统，我们比较了抗磷脂抗体综合征 (APS) 血栓形成患者与健康对照组中还原型 FXI 的量，并发现 APS 患者的还原型 FXI 水平更高。这可能对理解 FXI 对 APS 血栓形成的贡献以及血浆中还原型 FXI 水平升高的患者易发生血栓形成具有重要意义。
