Department of Ophthalmology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Acta Pharmacol Sin. 2023 Apr;44(4):897-912. doi: 10.1038/s41401-022-01005-2. Epub 2022 Oct 24.
Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular eye diseases, but responses are incomplete in some patients. Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. JP1, derived from an optimized seven-amino-acid fragment of JWA protein, is a polypeptide specifically targeting integrin αVβ3. In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization (CNV) and retinal vascular leakage. CNV mice received a single intravitreal (IVT) injection of JP1 (10, 20, 40 µg) or ranibizumab (RBZ, 10 µg). We showed that JP1 injection dose-dependently inhibited laser-induced CNV; the effect of RBZ was comparable to that of 20 µg JP1; a combined IVT injection of JP1 (20 μg) and RBZ (5 μg) exerted a synergistic effect on CNV. In the 3rd month after streptozotocin injection, diabetic mice receiving IVT injection of JP1 (40 µg) or RBZ (10 µg) once a week for 4 weeks showed significantly suppressed retinal vascular leakage. In both in vivo and in vitro experiments, JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells, and angiogenesis via modulating MEK1/2-SP1-integrin αVβ3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells. In addition, intraperitoneal injection of JP1 (1, 5 or 10 mg) once every other day for 3 times also dose-dependently inhibited CNV. After intraperitoneal injection of FITC-labeled JP1 (FITC-JP1) or FITC in laser-induced CNV mice, the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group, compared with that in FITC group, confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion. We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.
抗血管内皮生长因子（VEGF）药物彻底改变了新生血管性眼病的治疗方法，但在一些患者中反应并不完全。最近的证据表明，整合素参与了新生血管性年龄相关性黄斑变性和糖尿病性视网膜病变的发病机制。JP1 源自 JWA 蛋白的优化的七氨基酸片段，是一种专门针对整合素 αVβ3 的多肽。在这项研究中，我们评估了 JP1 对激光诱导脉络膜新生血管（CNV）和视网膜血管渗漏的疗效。CNV 小鼠接受单次玻璃体内（IVT）注射 JP1（10、20、40μg）或雷珠单抗（RBZ，10μg）。我们表明，JP1 注射剂量依赖性地抑制激光诱导的 CNV；RBZ 的作用与 20μg JP1 相当；JP1（20μg）和 RBZ（5μg）的联合 IVT 注射对 CNV 具有协同作用。在链脲佐菌素注射后的第 3 个月，每周接受一次 IVT 注射 JP1（40μg）或 RBZ（10μg）的糖尿病小鼠显示出明显抑制的视网膜血管渗漏。在体内和体外实验中，JP1 通过抑制小胶质细胞中的 ROS/NF-κB 信号转导以及通过调节 MEK1/2-SP1-整合素 αVβ3 和 TRIM25-SP1-MMP2 轴在血管内皮细胞中发挥作用，来对抗氧化应激和炎症，从而抑制血管生成。此外，每隔一天腹膜内注射 JP1（1、5 或 10mg）一次，连续 3 次，也呈剂量依赖性抑制 CNV。在激光诱导的 CNV 小鼠中腹膜内注射 FITC 标记的 JP1（FITC-JP1）或 FITC 后，与 FITC 组相比，CNV 病变中的荧光强度在 FITC-JP1 组中明显增加，证实 JP1 可以穿透血视网膜屏障以靶向 CNV 病变。我们得出结论，JP1 可用于设计新型 CNV 靶向治疗药物，可能替代当前的侵入性眼内注射。
