A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor.

Deokho Lee,Toshihide Kurihara,Heonuk Jeong,Jing Wu,Chiho Shoda,Hirokazu Kawagishi,Yukihiro Miwa,Kazuo Tsubota

doi:10.3390/biom10101405

Deokho Lee, Toshihide Kurihara + Show 6 more

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https://doi.org/10.3390/biom10101405

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Journal: Biomolecules	Publication Date: Oct 4, 2020
Citations: 23	License type: CC BY 4.0

Affiliation: Keio University, Shizuoka University, Nihon University

Abstract

Neovascular retinal degeneration is a leading cause of blindness in advanced countries. Anti-vascular endothelial growth factor (VEGF) drugs have been used for neovascular retinal diseases; however, anti-VEGF drugs may cause the development of chorioretinal atrophy in chronic therapy as they affect the physiological amount of VEGF needed for retinal homeostasis. Hypoxia-inducible factor (HIF) is a transcription factor inducing VEGF expression under hypoxic and other stress conditions. Previously, we demonstrated that HIF was involved with pathological retinal angiogenesis in murine models of oxygen-induced retinopathy (OIR), and pharmacological HIF inhibition prevented retinal neovascularization by reducing an ectopic amount of VEGF. Along with this, we attempted to find novel effective HIF inhibitors. Compounds originally isolated from mushroom-forming fungi were screened for prospective HIF inhibitors utilizing cell lines of 3T3, ARPE-19 and 661W. A murine OIR model was used to examine the anti-angiogenic effects of the compounds. As a result, 2-azahypoxanthine (AHX) showed an inhibitory effect on HIF activation and suppressed Vegf mRNA upregulation under CoCl2-induced pseudo-hypoxic conditions. Oral administration of AHX significantly suppressed retinal neovascular tufts in the OIR model. These data suggest that AHX could be a promising anti-angiogenic agent in retinal neovascularization by inhibiting HIF activation.

Highlights

Vascular diseases of the retina, including diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity and vessel occlusions, are major causes of vision loss worldwide [1,2]
We previously reported that Hypoxia-inducible factor (HIF) inhibitors, from anti-cancer drugs to natural marine products, suppressed retinal neovascularization and ectopic vascular endothelial growth factor (VEGF) expression in murine models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) [9,10,11]
Nine compounds originally from mushroom-forming fungi were obtained and screened for HIF inhibitory activity via HIF luciferase assay (Table 2). 200 μM of CoCl2 was used to induce HIF activation, and 1 mM of topotecan and 1 mM of doxorubicin were used as expected positive controls for HIF inhibition

Summary

Introduction

Vascular diseases of the retina, including diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity and vessel occlusions, are major causes of vision loss worldwide [1,2]. The interruption of VEGF signaling has been a good pharmacological target for the treatment of neovascular retinal diseases [3,4]. Anti-VEGF therapies have been widely used to treat pathological angiogenesis in the retina [5]. The small doses used for these diseases and the intravitreal route of the administration may limit systemic side effects, the drugs in chronic therapies can penetrate into blood circulation and alter the systemic or local VEGF levels which may be required for normal vascular and neuronal maintenance [5]. Many researchers have aimed to develop novel treatments that will help to prevent or suppress pathologic ocular neovascularization without affecting the systemic or local physiological amount of VEGF, or at least minimizing the adverse effects of the current therapies

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