Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan.
Neurochem Int. 2019 Sep;128:21-31. doi: 10.1016/j.neuint.2019.03.008. Epub 2019 Mar 11.
Neovascular retinal diseases are the leading causes of blindness in advanced countries. To date, anti-VEGF (vascular endothelial growth factor) drugs are clinically effective and widely used for these diseases. However, recent animal and clinical studies reported that potent and long-term VEGF antagonism may induce chorioretinal atrophy. Thus, physiological amount of VEGF is required for the homeostasis in the retina. Hypoxia-inducible factors (HIFs) are transcription factors located upstream of VEGF. We hypothesized that ectopically stabilized HIFs induce pathological amount of VEGF involved with retinal neovascularization. Therefore, HIF inhibition could be an alternative therapeutic candidate targeting the pathological amount of VEGF while holding a physiological amount of VEGF. To test this hypothesis, topotecan and doxorubicin, HIF inhibitors with different mechanisms were administered to the murine oxygen-induced retinopathy (OIR) model. We found that both topotecan and doxorubicin significantly prevented pathological but not physiological neovascularization in OIR. Furthermore, impaired visual function observed in OIR can also be suppressed by administering topotecan. These data suggested that HIF inhibition may be effective for pathological angiogenesis and neurodegeneration of the retina.
新生血管性视网膜疾病是发达国家致盲的主要原因。迄今为止,抗血管内皮生长因子(VEGF)药物在临床上具有疗效,并广泛用于治疗这些疾病。然而,最近的动物和临床研究报告称,强效且长期的 VEGF 拮抗作用可能会诱导脉络膜视网膜萎缩。因此,视网膜的内稳态需要生理量的 VEGF。缺氧诱导因子(HIFs)是位于 VEGF 上游的转录因子。我们假设异位稳定的 HIFs 会诱导与视网膜新生血管形成相关的病理性 VEGF 量。因此,抑制 HIF 可能是一种替代治疗候选方案,可以针对病理性 VEGF 量,同时保持生理性 VEGF 量。为了验证这一假设,我们在小鼠氧诱导的视网膜病变(OIR)模型中给予了拓扑替康和多柔比星这两种具有不同作用机制的 HIF 抑制剂。我们发现,拓扑替康和多柔比星均可显著预防 OIR 中的病理性新生血管形成,但不能预防生理性新生血管形成。此外,给予拓扑替康还可以抑制 OIR 中观察到的视觉功能障碍。这些数据表明,抑制 HIF 可能对视网膜病理性血管生成和神经退行性变有效。