Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 24341, Republic of Korea.
National Research Laboratory for Molecular Virology, Department of Pathology, School of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
Biomed Pharmacother. 2021 Feb;134:111110. doi: 10.1016/j.biopha.2020.111110. Epub 2020 Dec 15.
Targeting the vascular endothelial growth factor (VEGF)/its receptor-2 (VEGFR-2) system has become a mainstay of treatment for many human diseases, including retinal diseases. We examined the therapeutic effect of recently developed N-acetylated Arg-Leu-Tyr-Glu (Ac-RLYE), a human plasminogen kringle-5 domain-derived VEGFR-2 antagonists, on the pathogenesis of diabetic retinopathy. Ac-RLYE inhibited VEGF-A-mediated VEGFR-2 activation and endothelial nitric oxide synthase (eNOS)-derived NO production in the retinas of diabetic mice. In addition, Ac-RLYE prevented the disruption of adherens and tight junctions and vascular leakage by inhibiting S-nitrosylation of β-catenin and tyrosine nitration of p190RhoGAP in the retinal vasculature of diabetic mice. Peptide treatment preserved the pericyte coverage of retinal capillaries by upregulating angiopoietin-2. These results suggest that Ac-RLYE potentially prevents blood-retinal barrier breakdown and vascular leakage by antagonizing VEGFR-2; Ac-RLYE can be used as a potential therapeutic drug for the treatment of diabetic retinopathy.
靶向血管内皮生长因子 (VEGF)/其受体-2 (VEGFR-2) 系统已成为许多人类疾病（包括视网膜疾病）治疗的主要手段。我们研究了最近开发的 N-乙酰化精氨酸-亮氨酸-酪氨酸-谷氨酸 (Ac-RLYE) 对糖尿病性视网膜病变发病机制的治疗效果，它是一种人纤溶酶原kringle-5 结构域衍生的 VEGFR-2 拮抗剂。Ac-RLYE 抑制了糖尿病小鼠视网膜中 VEGF-A 介导的 VEGFR-2 激活和内皮型一氧化氮合酶 (eNOS) 衍生的 NO 产生。此外，Ac-RLYE 通过抑制 β-连环蛋白的 S-亚硝基化和 p190RhoGAP 的酪氨酸硝化，防止了黏附连接和紧密连接的破坏以及血管渗漏，在糖尿病小鼠的视网膜血管中。肽处理通过上调血管生成素-2 来维持视网膜毛细血管周细胞的覆盖。这些结果表明，Ac-RLYE 通过拮抗 VEGFR-2 有可能预防血视网膜屏障的破坏和血管渗漏；Ac-RLYE 可用作治疗糖尿病性视网膜病变的潜在治疗药物。
