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Suppression of Choroidal Neovascularization by Thioredoxin-1 via Interaction with Complement Factor H

¹From the Department of Ophthalmology and Visual Science, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; ²Department of Ophthalmology, Shimane University School of Medicine, Shimane, Japan; ³Thioredoxin Project, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan; ⁴Human Stress Signal Research Center, National Institute of Advanced Industrial Science and Technology, Osaka, Japan; and ⁵Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.

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 wild-type 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.