June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
APE1/Ref-1 is overexpressed and colocalizes with neovascular tufts and hypoxic regions in the oxygen-induced retinopathy mouse model
Author Affiliations & Notes
  • Gabriella D Hartman
    Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Anbukkarasi Muniyandi
    Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Mark R Kelley
    Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Timothy William Corson
    Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Footnotes
    Commercial Relationships   Gabriella Hartman None; Anbukkarasi Muniyandi None; Mark Kelley Ocuphire Pharma, Code C (Consultant/Contractor), Apexian Pharmaceutical, Code C (Consultant/Contractor), US 16/968,009, Code P (Patent); Timothy Corson US 16/968,009, Code P (Patent)
  • Footnotes
    Support  NIH/NEI R01EY031939; Research to Prevent Blindness (RPB)
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 269 – F0314. doi:
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      Gabriella D Hartman, Anbukkarasi Muniyandi, Mark R Kelley, Timothy William Corson; APE1/Ref-1 is overexpressed and colocalizes with neovascular tufts and hypoxic regions in the oxygen-induced retinopathy mouse model. Invest. Ophthalmol. Vis. Sci. 2022;63(7):269 – F0314.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Current treatments for retinal neovascularization as seen in proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) include intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics. However, anti-VEGF biologics are accompanied by tachyphylaxis, high treatment burden, and complications, corroborating an unmet need for novel therapeutic targets. A promising therapeutic target for treatment of PDR and ROP is the redox transcriptional regulatory function of the protein apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1). Ref-1 activity has been implicated in multiple relevant pathways involved in retinal neovascularization including angiogenesis, inflammation, and stress response. First-generation Ref-1 redox inhibitor APX3330 is already in phase II clinical trials for DR and diabetic macular edema (DME). However, the expression of Ref-1 has yet to be fully characterized in retinal neovascular disease. We aimed to assess Ref-1 expression in the murine oxygen-induced retinopathy (OIR) model to increase understanding of Ref-1’s role in retinal neovascularization.

Methods : Neonatal mice and dams were exposed to hyperoxia (75% O2) or room air for 5 days (P7-P12). Mice were injected with pimonidazole for visualization of hypoxic regions two hours before euthanasia and enucleation at P12, P15, and P17. Retinal flatmounts were coimmunostained for Ref-1, vasculature (isolectin B4), and hypoxia (Hypoxyprobe). Spatial and temporal expression of Ref-1 was analyzed by confocal microscopy.

Results : Ref-1 colocalized with vasculature and hypoxic regions in the OIR model. Mean fluorescent intensity (MFI) of Ref-1 in OIR eyes was higher compared to normoxia control eyes at each time point (p<0.0001, two-way ANOVA, Tukey’s post hoc test). Ref-1 colocalized with neovascular tufts, and Ref-1 expression was absent in vaso-obliterated areas of the retina.

Conclusions : Previous data revealed that Ref-1 inhibition blocks laser-induced choroidal neovascularization (L-CNV). Here, we revealed that Ref-1 is highly expressed in pathological angiogenic tufts in the murine OIR retina, suggesting that Ref-1 is likewise important for retinal neovascularization, thus providing context for new potential therapeutic use in PDR and/or ROP.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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