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.

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一种神奇的化学物质作为 HIF 抑制剂抑制视网膜血管生成

新生血管性视网膜变性是发达国家失明的主要原因。抗血管内皮生长因子（VEGF）药物已用于新生血管性视网膜疾病；然而，在慢性治疗中，抗 VEGF 药物可能会导致脉络膜视网膜萎缩，因为它们会影响视网膜稳态所需的 VEGF 的生理量。缺氧诱导因子 (HIF) 是一种在缺氧和其他应激条件下诱导 VEGF 表达的转录因子。以前，我们证明 HIF 与氧诱导视网膜病变 (OIR) 小鼠模型中的病理性视网膜血管生成有关，药理学 HIF 抑制通过减少异位 VEGF 量来防止视网膜新生血管形成。与此同时，我们试图寻找新型有效的 HIF 抑制剂。利用 3T3、ARPE-19 和 661W 细胞系，对最初从形成蘑菇的真菌中分离出来的化合物进行了潜在的 HIF 抑制剂筛选。使用鼠 OIR 模型来检查化合物的抗血管生成作用。结果，2-氮杂次黄嘌呤 (AHX) 显示出对 HIF 活化的抑制作用并抑制在 CoCl ₂诱导的假缺氧条件下Vegf mRNA 上调。AHX 的口服给药显着抑制了 OIR 模型中的视网膜新生血管簇。这些数据表明，AHX 可能通过抑制 HIF 激活而成为视网膜新生血管形成中一种有前途的抗血管生成剂。