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<p>Reduction–oxidation factor-1 or apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1) is a crucial redox-sensitive activator of transcription factors such as NF-κB, HIF-1α, STAT-3 and others. It could contribute to key features of ocular neovascularization including inflammation and angiogenesis; these underlie diseases like neovascular age-related macular degeneration (nAMD). We previously revealed a role for Ref-1 in the growth of ocular endothelial cells and in choroidal neovascularization (CNV). Here, we set out to further explore Ref-1 in neovascular eye disease. Ref-1 was highly expressed in human nAMD, murine laser-induced CNV and <i>Vldlr</i><sup>−/−</sup> mouse subretinal neovascularization (SRN). Ref-1’s interaction with a redox-specific small molecule inhibitor, APX2009, was shown by NMR and docking. This compound blocks crucial angiogenic features in multiple endothelial cell types. APX2009 also ameliorated murine laser-induced choroidal neovascularization (L-CNV) when delivered intravitreally. Moreover, systemic APX2009 reduced murine SRN and downregulated the expression of Ref-1 redox regulated HIF-1α target carbonic anhydrase 9 (CA9) in the <i>Vldlr</i><sup>−/−</sup> mouse model. Our data validate the redox function of Ref-1 as a critical regulator of ocular angiogenesis, indicating that inhibition of Ref-1 holds therapeutic potential for treating nAMD.</p>

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Ref-1 is overexpressed in neovascular eye disease and targetable with a novel inhibitor

  • 期刊论文

  • 发表日期：

    2025年1月5日

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  • Anbukkarasi Muniyandi,
  • Gabriella D. Hartman,
  • Kamakshi Sishtla,
  • Ratan Rai,
  • Cátia Gomes,
  • Kristina Day,
  • Yang Song,
  • Andi R. Masters,
  • Sara K. Quinney,
  • Xiaoping Qi,
  • Hailey Woods,
  • Michael E. Boulton,
  • Jason S. Meyer,
  • Jonah Z. Vilseck,
  • Millie M. Georgiadis,
  • Mark R. Kelley,
  • Timothy W. Corson

摘要

Reduction–oxidation factor-1 or apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1) is a crucial redox-sensitive activator of transcription factors such as NF-κB, HIF-1α, STAT-3 and others. It could contribute to key features of ocular neovascularization including inflammation and angiogenesis; these underlie diseases like neovascular age-related macular degeneration (nAMD). We previously revealed a role for Ref-1 in the growth of ocular endothelial cells and in choroidal neovascularization (CNV). Here, we set out to further explore Ref-1 in neovascular eye disease. Ref-1 was highly expressed in human nAMD, murine laser-induced CNV and Vldlr−/− mouse subretinal neovascularization (SRN). Ref-1’s interaction with a redox-specific small molecule inhibitor, APX2009, was shown by NMR and docking. This compound blocks crucial angiogenic features in multiple endothelial cell types. APX2009 also ameliorated murine laser-induced choroidal neovascularization (L-CNV) when delivered intravitreally. Moreover, systemic APX2009 reduced murine SRN and downregulated the expression of Ref-1 redox regulated HIF-1α target carbonic anhydrase 9 (CA9) in the Vldlr−/− mouse model. Our data validate the redox function of Ref-1 as a critical regulator of ocular angiogenesis, indicating that inhibition of Ref-1 holds therapeutic potential for treating nAMD.