Suppression of choroidal neovascularization by thioredoxin-1 via interaction with complement factor H

Invest Ophthalmol Vis Sci. 2008 Nov;49(11):5118-25. doi: 10.1167/iovs.07-1659. Epub 2008 May 30.

Abstract

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

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Choroidal Neovascularization / metabolism
  • Choroidal Neovascularization / pathology
  • Choroidal Neovascularization / prevention & control*
  • Complement Factor H / drug effects
  • Complement Factor H / metabolism*
  • Disease Models, Animal
  • Electrophoresis, Gel, Two-Dimensional
  • Humans
  • Immunohistochemistry
  • Injections, Intraperitoneal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Thioredoxins / administration & dosage
  • Thioredoxins / therapeutic use*

Substances

  • Thioredoxins
  • Complement Factor H