Suppression of Choroidal Neovascularization by Thioredoxin-1 via Interaction with Complement Factor H
Suppression of Choroidal Neovascularization by Thioredoxin-1 via Interaction with Complement Factor H
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DOI：
10.1167/iovs.07-1659
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发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Nakamura, Hajime
中科院分区：
文献类型：
--
作者：
Inomata, Yasuya;Tanihara, Hidenobu;Nakamura, Hajime
目的.目的探讨硫氧还蛋白-1（TRX-1）在脉络膜新生血管（CNV）形成中的作用。在野生型和过表达人TRX-1（TRX-1 Tg）的转基因小鼠中，通过眼底激光凝固诱导CNV。用TRX-1、突变体TRX或媒介物腹膜内注射小鼠。用凝集素染色法观察CNV的发生率。用免疫组化和Western blotting法检测激光损伤后白细胞募集和C3 b沉积。此外，TRX-1相关的蛋白质从人血浆中分离的二维凝胶电泳与使用的柱耦合的突变体TRX-1，并通过质谱和蛋白质组学分析进行了鉴定。通过液相法测定补体激活。与野生型小鼠（85.7%）相比，TRX-1 Tg小鼠（56.1%）和用TRX-1处理的C57 B/ 6小鼠（46.7%）中激光诱导的CNV发生率降低，但突变型TRX-1（79.2%）中未降低。此外，TRX-1处理的小鼠中白细胞募集被阻止;这些小鼠和TRX-1 Tg小鼠中的C3 b沉积减少。在人血浆中，与TRX-1相关的五种蛋白质被鉴定为载脂蛋白A-I、清道夫受体的CD 5抗原样成员、富含半胱氨酸的超家族纤维蛋白原、白蛋白和补体因子H（CFH）。TRX-1对旁路途径C3转化酶有抑制作用，其抑制作用与CFH有相加作用。这些发现表明TRX-1与CFH相互作用，调节补体活性，并抑制CNV，提示AMD的新的预防和干预治疗策略。（Invest Ophthalmol维斯科学。2008; 49：5118 - 5125）DOI：10.1167/ iovs. 07-1659
PURPOSE. To examine the role of thioredoxin-1 (TRX-1), an endogenous protein with a variety of redox-related roles, in the formation of choroidal neovascularization (CNV).METHODS. CNV was induced by laser photocoagulation of the ocular fundus in wild-type and transgenic mice overexpressing human TRX-1 (TRX-1 Tg). Mice were injected intraperitoneally with TRX-1, mutant TRX, or vehicle. The incidence of CNV was evaluated by lectin staining. Leukocyte recruitment and C3b deposition after laser injury were determined by immunohistochemistry and Western blotting. Moreover, TRX-1-associated proteins from human plasma were isolated by two-dimensional gel electrophoresis with the use of a column coupled with a mutant TRX-1 and were identified by mass spectrometry and proteomics analysis. Complement activation was determined by a fluid-phase method.RESULTS. The incidence of laser-induced CNV was reduced in TRX-1 Tg mice (56.1%) and in C57B/ 6 mice treated with TRX-1 (46.7%) but not in mutant TRX-1 (79.2%) compared with wildtype mice (85.7%). Furthermore, leukocyte recruitment was prevented in TRX-1-treated mice; C3b deposition was decreased in these and TRX-1 Tg mice. In human plasma, five proteins associated with TRX-1 were identified as apolipoprotein A-I, the CD5 antigen-like member of the scavenger receptor, cysteine-rich superfamily fibrinogen, albumin, and complement factor H (CFH). TRX-1 inhibited the alternative pathway C3 convertase, and its effect was additive with CFH.CONCLUSIONS. These findings show that TRX-1 interacts with CFH, regulates complement activity, and inhibits CNV, suggesting novel preventive and interventional therapeutic strategies for AMD. (Invest Ophthalmol Vis Sci. 2008; 49: 5118 -5125) DOI: 10.1167/ iovs. 07-1659