March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Regulation of Retinal Vascular Permeability by Inhibition of APE1/Ref-1 Redox Activity with APX3330
Author Affiliations & Notes
  • Yue Li
    Department of Ophthalmology, Henry Ford Health System, Detroit, Michigan
  • Xiuli Liu
    Department of Ophthalmology, Henry Ford Health System, Detroit, Michigan
  • Tongrong Zhou
    Department of Ophthalmology, Henry Ford Health System, Detroit, Michigan
  • Mark R. Kelley
    Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
  • Paul Edwards
    Department of Ophthalmology, Henry Ford Health System, Detroit, Michigan
  • Hua Gao
    Department of Ophthalmology, Henry Ford Health System, Detroit, Michigan
  • Xiaoxi Qiao
    Department of Ophthalmology, Henry Ford Health System, Detroit, Michigan
  • Footnotes
    Commercial Relationships  Yue Li, None; Xiuli Liu, None; Tongrong Zhou, None; Mark R. Kelley, None; Paul Edwards, None; Hua Gao, None; Xiaoxi Qiao, None
  • Footnotes
    Support  NIH National Eye Institute EY019784, International Retinal Research Foundation, Midwest Eye Bank, Fund for Henry Ford Hospital, Alliance for Vision Research.
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 5558. doi:
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      Yue Li, Xiuli Liu, Tongrong Zhou, Mark R. Kelley, Paul Edwards, Hua Gao, Xiaoxi Qiao; Regulation of Retinal Vascular Permeability by Inhibition of APE1/Ref-1 Redox Activity with APX3330. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5558.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : The redox activity of APE1/Ref-1 plays an important role in retinal vascular endothelial cell (RVEC) proliferation and normal function. We previously reported that a small molecular APE1/Ref-1 redox inhibitor, APX3330,can inhibit RVEC angiogenesis. The purpose of this study was to determine the effect of APX3330 on retino-choroidal vascular permeability in vitro and in vivo.

Methods: : Early passages of human RVECs and murine RVECs were grown in 3.0 μm pore size Transwell system. In vitro permeability changes of the cell monolayer were analyzed using FITC-dextran tracers. Very-low-density lipoprotein receptor knockout (vldlr-/-) mutant mice with spontaneous subretinal neovascularization and laser-induced choroidal neovascularization (CNV) mice were used for in vivo permeability assays. Expression of VEGF and VE-cadherin were assessed by ELISA and western.

Results: : Administration of APX3330 can significantly (p < 0.05) attenuate TNF-α induced increase of both human and murine RVEC monolayer permeability through Transwell systems. Immunoblot assay indicated a 14% increase of VE-cadherin expression upon APX3330 treatment in RVEC monolayer. However, APX3330 treatment did not directly alter VEGF expression of the cells. A single intravitreal injection of APX3330 led to a 25% reduction of choroidal neovascular permeability in laser-induced CNV mice. Preliminary data also indicated a decreased trend of retinal vascular permeability after a single intravitreal dosage of APX3330 in vldlr-/- mice.

Conclusions: : Specific inhibition of the redox activity of APE1/Ref-1 with APX3330 led to decreased retino-choroidal vascular permeability in vitro and in vivo. Inhibiting the redox function of APE1/Ref-1 may offer a novel approach to control hyper-vasopermeability in the conditions such as retino-choroidal neovascularization and diabetic retinopathy.

Keywords: drug toxicity/drug effects • retinal neovascularization • choroid: neovascularization 
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