Inhibition of APE1/Ref-1 redox activity with APX3330 blocks retinal angiogenesis in vitro and in vivo

Aihua Jiang, Hua Gao, Mark R. Kelley, Xiaoxi Qiao

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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 μM) 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.

Original languageEnglish (US)
Pages (from-to)93-100
Number of pages8
JournalVision Research
Volume51
Issue number1
DOIs
StatePublished - Jan 1 2011

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Keywords

  • Age-related macular degeneration
  • Angiogenesis
  • APE1/Ref-1
  • APX3330
  • RAP-like neovascularization
  • Redox inhibitor
  • Reduction-oxidation regulation

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems

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