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A. Jiang, M. R. Kelley, H. Gao, X. Qiao; Selective Blocking of APE1/Ref-1 Redox Function by a Novel Compound, APX3330 Inhibits Retinal Angiogenesis in vitro and in vivo. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2977.
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Although several of APE1/Ref-1 downstream transcription factors are known to be involved in angiogenesis, the role of APE1/Ref-1 in retinal angiogenesis is not clear. In this study, we examined the expression of APE1/Ref-1 in the retina and retinal vascular cells, and evaluated the potential of APE1/Ref-1 as a new therapeutic target for inhibition of retinal angiogenesis.
Western blot was used to determine the expression of APE1/Ref-1. Effects of blocking APE1/Ref-1 redox function by APX3330 on retinal vascular endothelial cells (RVECs) and retinal pericytes (RPCs) growth were evaluated by MTS assay, tube formation assay, and xCELLigence System. A mutant VLDL receptor knockout (vldlr-/-) mouse model with subretinal neovascularization (SNV) was used to test the treatment effect of intravitreal APX3330.
Western blot revealed high levels of APE1/Ref-1 expression in the retina, choroid/RPE, and in purified RVECs and RPCs of mouse eyes. APX3330 dose-dependently inhibited the proliferation and tube formation of RVECs in vitro. The dose range for statistic significant inhibition is 1~10 µM. Similar dose-dependent inhibition of APX3330 was also found in the growth of RPCs. Using the xCELLigence System which dynamically monitors the impedance of cultured cells, RVECs isolated from both wildtype and vldlr-/- mice were potently inhibited by APX3330 despite significant genotypic differences in the growth pattern. There is a trend of stronger inhibition in vldlr-/- RVECs than that in wildtype RVECs. In vldlr-/- mice, single APX3330 intravitreal injection at the onset of SNV significantly reduced the total number of SNV in one week. Significant improved rate (>20% reduction) is 75%.
APE1/Ref-1 is expressed in the retina particularly in retinal vascular cells. Blocking APE1/Ref-1 with APX3330 potently inhibited the growth of both RVEC and RPC in vitro and significantly reduced SNV in vldlr-/- mice. Inhibiting the redox function of APE1/Ref-1 may offer a novel approach to control retinal angiogenesis for AMD treatment.
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