Browsing by Author "Miller, William P."

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    Ref‐1 redox activity regulates retinal neovascularization by modulating transcriptional activation of HIF‐1α
    (Wiley, 2025) Hartman, Gabriella D.; Muniyandi, Anbukkarasi; Sishtla, Kamakshi; Kpenu, Eyram K.; Miller, William P.; Kaplan, Bryan A.; Kim, Leo A.; Liu, Sheng; Wan, Jun; Qi, Xiaoping; Boulton, Michael E.; Kelley, Mark R.; Corson, Timothy W.; Ophthalmology, School of Medicine
    Retinal neovascularization impairs visual function and is a hallmark of several neovascular eye diseases, including retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Current treatments include intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, but these therapeutics are often accompanied by high treatment burden and resistance to therapy. Prior studies indicate that APE1/Ref-1, a multifunctional protein with both endonuclease (APE1) and redox-mediated transcriptional regulatory activity (Ref-1), activates multiple pro-angiogenic and pro-inflammatory signaling pathways by chemically reducing key cysteine residues in transcription factors, thereby activating them. Here, we investigated the previously unexplored role of Ref-1 in retinal neovascularization. We demonstrate that Ref-1 is highly expressed in endothelial cells in human PDR and in the oxygen-induced retinopathy (OIR) mouse model of retinal neovascularization. Ref-1 is also highly expressed in microglia and astrocytes in OIR. A small molecule Ref-1 redox inhibitor, APX2009, decreased retinal neovascularization in OIR after systemic delivery. In vitro, hypoxic endothelial cells did not exhibit upregulation of Ref-1 but rather increased Ref-1 nuclear localization. APX2009 decreased hypoxic endothelial cell proliferation and HIF-1α transcriptional activation. Thus, Ref-1 redox activity may be a novel therapeutic target for the treatment of retinal neovascularization, making APX2009 a promising systemic therapeutic approach for the treatment of vascular retinopathies such as ROP and PDR.