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

Autor: Muniyandi A; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA., Hartman GD; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA., Sishtla K; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada., Rai R; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Gomes C; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA., Day K; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA., Song Y; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA., Masters AR; Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA., Quinney SK; Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA., Qi X; Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL, USA., Woods H; Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA., Boulton ME; Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL, USA., Meyer JS; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA., Vilseck JZ; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA., Georgiadis MM; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA., Kelley MR; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA., Corson TW; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA. tim.corson@utoronto.ca.; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA. tim.corson@utoronto.ca.; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA. tim.corson@utoronto.ca.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. tim.corson@utoronto.ca.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA. tim.corson@utoronto.ca.; Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada. tim.corson@utoronto.ca.; Department of Ophthalmology and Vision Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. tim.corson@utoronto.ca.
Jazyk: angličtina
Zdroj: Angiogenesis [Angiogenesis] 2025 Jan 05; Vol. 28 (1), pp. 11. Date of Electronic Publication: 2025 Jan 05.
DOI: 10.1007/s10456-024-09966-0
Abstrakt: 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.
Competing Interests: Declarations. Conflict of interest: MRK and TWC are named inventors on patents related to this work, licensed to Apexian Pharmaceuticals and Opus Genetics. MRK is a consultant to Opus Genetics and CSO and cofounder of Apexian Pharmaceuticals, which developed APX3330 for oncology, as well as APX2009 investigated in this manuscript. The other authors declare no conflicts of interest. Neither Apexian Pharmaceuticals nor Opus Genetics had any input or control over the contents of this manuscript.
(© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze: MEDLINE
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