Li, YueLiu, XiuliZhou, TongrongKelley, Mark R.Edwards, Paul A.Gao, HuaQiao, Xiaoxi2016-05-042016-05-042014-07Li, Y., Liu, X., Zhou, T., Kelley, M. R., Edwards, P. A., Gao, H., & Qiao, X. (2014). Suppression of Choroidal Neovascularization Through Inhibition of APE1/Ref-1 Redox Activity. Investigative Ophthalmology & Visual Science, 55(7), 4461–4469. http://doi.org/10.1167/iovs.14-144511552-5783https://hdl.handle.net/1805/9516PURPOSE: The redox function of APE1/Ref-1 is a key regulator in pathological angiogenesis, such as retinal neovascularization and tumor growth. In this study, we examined whether inhibition of APE1/Ref-1 redox function by a small molecule inhibitor E3330 suppresses experimental choroidal neovascularization (CNV) in vitro and in vivo. METHODS: Primate choroid endothelial cells (CECs) received treatment of 0 to 100 μM E3330 alone or cotreatment of E3330 and 500 μg/mL anti-VEGF antibody bevacizumab. Choroid endothelial cell angiogenic function was examined by cell proliferation, migration, and tube formation assays. The effects of E3330 on NF-κB and STAT3 signaling pathways were determined by reporter gene assay, Western blot, and ELISA. Laser-induced CNV mouse model was used to test the effects of E3330 in vivo. Potential toxicity of E3330 was evaluated by TUNEL assay. RESULTS: The E3330 of 25 to 100 μM dose-dependently suppressed CEC proliferation, migration, and tube formation, in the absence of noticeable cell toxicity. Lower doses of E3330 (10-20 μM) reduced the transcriptional activity of NF-κB and STAT3 without affecting protein phosphorylation of both molecules. At the same time, E3330 downregulated MCP-1 production in CECs. The antiangiogenic effect of E3330 was comparable and additive to bevacizumab. The E3330 effectively attenuated the progression of laser-induced CNV in mice after a single intravitreal injection. CONCLUSIONS: The APE1/Ref-1 redox function regulates multiple transcription factors and inflammatory molecules, and is essential for CEC angiogenesis. Specific inhibition of APE1/Ref-1 redox function with E3330 may represent a promising novel treatment for wet AMD.en-USPublisher PolicyBenzoquinonespharmacologyChoroidal Neovascularizationprevention & controlDNA-(Apurinic or Apyrimidinic Site) Lyaseantagonists & inhibitorsDisease Models, AnimalPropionatesArticle