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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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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.
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.
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.
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.
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