Department of Pharmacology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, 80424 Kaohsiung, Taiwan.
International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan 70101, Taiwan.
Biomed Pharmacother. 2023 Sep;165:115109. doi: 10.1016/j.biopha.2023.115109. Epub 2023 Jul 3.
Retinal neovascularization (RNV) and cell apoptosis observed in retinopathy are the most common cause of vision loss worldwide. Increasing vascular endothelial growth factor (VEGF), which was driven by hypoxia or inflammation, would result in RNV. This study investigated the anti-inflammatory and anti-apoptotic xanthine-based derivative KMUP-1 on hypoxia-induced conditions in vitro and in vivo. In the oxygen-induced retinopathy animal model, KMUP-1 mitigated vaso-obliteration and neovascularization. In the cell model of hypoxic endothelium cultured at 1% O, KMUP-1 inhibited endothelial migration and tube formation and had no cytotoxic effect on cell growth. Upregulation of pro-angiogenic factors, HIF-1α and VEGF, and pro-inflammatory cytokines, IL-1β and TNF-α, expression in the retinal-derived endothelial cells, RF/6 A cells, upon hypoxia stimulation, was suppressed by KMUP-1 treatment. RF/6 A cells treated with KMUP-1 showed a reduction of PI3K/Akt, ERK, and RhoA/ROCKs signaling pathways and induction of protective pathways such as eNOS and soluble guanylyl cyclase at 1% O. Furthermore, KMUP-1 decreased the expression of VEGF, ICAM-1, TNF-α, and IL-1β and increased the BCL-2/BAX ratio in the oxygen-induced retinopathy mouse retina samples. In conclusion, the results of this study suggest that KMUP-1 has potential therapeutic value in retinopathy due to its triple effects on anti-angiogenesis, anti-inflammation, and anti-apoptosis in hypoxic endothelium.
视网膜新生血管（RNV）和细胞凋亡是全世界视力丧失的最常见原因，在视网膜病变中观察到。缺氧或炎症驱动的血管内皮生长因子（VEGF）的增加会导致 RNV。本研究探讨了基于黄嘌呤的抗炎和抗细胞凋亡衍生物 KMUP-1 在体外和体内缺氧条件下的作用。在氧诱导的视网膜病变动物模型中，KMUP-1 减轻了血管闭塞和新生血管形成。在培养于 1%O 的缺氧内皮细胞的细胞模型中，KMUP-1 抑制了内皮细胞迁移和管形成，并且对细胞生长没有细胞毒性。在视网膜衍生的内皮细胞 RF/6A 细胞中，缺氧刺激后上调的促血管生成因子 HIF-1α 和 VEGF 以及促炎细胞因子 IL-1β 和 TNF-α 的表达，被 KMUP-1 处理所抑制。用 KMUP-1 处理的 RF/6A 细胞显示 PI3K/Akt、ERK 和 RhoA/ROCKs 信号通路减少，并且在 1%O 下诱导保护途径如 eNOS 和可溶性鸟苷酸环化酶。此外，KMUP-1 降低了氧诱导的视网膜病变小鼠视网膜样本中 VEGF、ICAM-1、TNF-α 和 IL-1β 的表达，并增加了 BCL-2/BAX 比值。总之，本研究的结果表明，由于 KMUP-1 在缺氧内皮细胞中具有抗血管生成、抗炎和抗细胞凋亡的三重作用，因此它在视网膜病变中具有潜在的治疗价值。
