期刊
VISION RESEARCH
卷 51, 期 1, 页码 93-100出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.visres.2010.10.008
关键词
Age-related macular degeneration; RAP-like neovascularization; Angiogenesis; APE1/Ref-1; Reduction-oxidation regulation; Redox inhibitor; APX3330
资金
- Fight for Sight
- Reeve's Foundation
- American Health Assistance Foundation
- NIH, National Cancer Institute [CA106298, CA114571, CA121168]
- NIH National Eye Institute [R41 EY019784]
- Riley Children's Foundation
- CTSA [UL1RR025761]
- NATIONAL CANCER INSTITUTE [R01CA106298, R01CA114571, R01CA121168] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR025761] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R41EY019784] Funding Source: NIH RePORTER
This study examines the role of APE1/Ref-1 in the retina and its potential as a therapeutic target for inhibiting retinal angiogenesis. APE1/Ref-1 expression was quantified by Western blot. The role of APE1/Ref-1 redox function in endothelial cell in vitro angiogenesis was examined by treating retinal vascular endothelial cells (RVECs) with APX3330, a small molecule inhibitor of APE1/Ref-1 redox activity. In vitro methods included a proliferation assay, a transwell migration assay, a Matrigel tube formation assay, and a Real-Time Cell Analysis (RTCA) using the xCELLigence System. In vivo functional studies of APE1/Ref-1 were carried out by treating very low density lipoprotein (VLDL) receptor knockout mice (Vldlr(-/-)) with intravitreal injection of APX3330, and subsequent measurement of retinal angiomatous proliferation (RAP)-like neovascularization for one week. APE1/Ref-1 was highly expressed in the retina and in RVECs and pericytes in mice. APX3330 (1-10 mu M) inhibited proliferation, migration and tube formation of RVECs in vitro in a dose-dependent manner. Vldlr(-/-) RVECs were more sensitive to APX3330 than wild-type RVECs. In Vldlr(-/-) mice, a single intravitreal injection of APX3330 at the onset of RAP-like neovascularization significantly reduced RAP-like neovascularization development. APE1/Ref-1 is expressed in retinal vascular cells. APX3330 inhibits RVEC angiogenesis in vitro and significantly reduces RAP-like neovascularization in Vldlr(-/-) mice. These data support the conclusion that APE1/Ref-1 redox function is required for retinal angiogenesis. Thus, APE1/Ref-1 may have potential as a therapeutic target for treating neovascular age-related macular degeneration and other neovascular diseases. (C) 2010 Elsevier Ltd. All rights reserved.
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