Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Pharmacy Practice and Science II (Kitasato University East Hospital), Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
J Pharmacol Sci. 2018 Nov;138(3):203-208. doi: 10.1016/j.jphs.2018.10.004. Epub 2018 Oct 14.
Pathological retinal angiogenesis contributes to the pathogenesis of several ocular diseases. Valproic acid, a widely used antiepileptic drug, exerts anti-angiogenic effects by inhibiting histone deacetylase (HDAC). Herein, we investigated the effects of valproic acid and vorinostat, a HDAC inhibitor, on pathological retinal angiogenesis in mice with oxygen-induced retinopathy (OIR). OIR was induced in neonatal mice by exposure to 80% oxygen from postnatal day (P) 7 to P10 and to atmospheric oxygen from P10 to P15. Mice were subcutaneously injected with valproic acid, vorinostat, or vehicle once a day from P10 to P14. At P15, retinal neovascular tufts and vascular growth in the central avascular zone were observed in mice with OIR. Additionally, immunoreactivity for phosphorylated ribosomal protein S6 (pS6), an indicator of mammalian target of rapamycin (mTOR) activity, was detected in the neovascular tufts. Both valproic acid and vorinostat reduced the formation of retinal neovascular tuft without affecting vascular growth in the central avascular zone. Valproic acid reduced the pS6 immunoreactivity in neovascular tufts. Given that vascular endothelial growth factor (VEGF) activates mTOR-dependent pathways in proliferating endothelial cells of the neonatal mouse retina, these results suggest that valproic acid suppresses pathological retinal angiogenesis by interrupting VEGF-mTOR pathways.
病理性视网膜血管生成导致多种眼部疾病的发生。丙戊酸是一种广泛使用的抗癫痫药物，通过抑制组蛋白去乙酰化酶（HDAC）发挥抗血管生成作用。本研究旨在探讨丙戊酸和伏立诺他（一种 HDAC 抑制剂）对氧诱导视网膜病变（OIR）小鼠病理性视网膜血管生成的影响。通过在新生后第 7 天至第 10 天暴露于 80%氧气，并在第 10 天至第 15 天暴露于大气氧气，诱导新生小鼠发生 OIR。从第 10 天至第 14 天，每天对小鼠皮下注射丙戊酸、伏立诺他或载体。在第 15 天，观察到 OIR 小鼠的视网膜新生血管丛和中央无血管区的血管生长。此外，在新生血管丛中检测到磷酸化核糖体蛋白 S6（pS6）的免疫反应性，pS6 是雷帕霉素靶蛋白（mTOR）活性的标志物。丙戊酸和伏立诺他均可减少视网膜新生血管丛的形成，而不影响中央无血管区的血管生长。丙戊酸降低了新生血管丛中的 pS6 免疫反应性。鉴于血管内皮生长因子（VEGF）在新生鼠视网膜增殖内皮细胞中激活 mTOR 依赖性途径，这些结果表明，丙戊酸通过阻断 VEGF-mTOR 途径抑制病理性视网膜血管生成。
