Browsing by Author "Day, Kristina"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    Ref-1 is overexpressed in neovascular eye disease and targetable with a novel inhibitor
    (Springer, 2025-01-05) Muniyandi, Anbukkarasi; Hartman, Gabriella D.; Sishtla, Kamakshi; Rai, Ratan; Gomes, Cátia; Day, Kristina; Song, Yang; Masters, Andi R.; Quinney, Sara K.; Qi, Xiaoping; Woods, Hailey; Boulton, Michael E.; Meyer, Jason S.; Vilseck, Jonah Z.; Georgiadis, Millie M.; Kelley, Mark R.; Corson, Timothy W.; Pharmacology and Toxicology, School of Medicine
    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.