Yamagishi Sho-ichi, Nakamura Kazuo, Matsui Takanori, Inagaki Yosuke, Takenaka Katsuhiko, Jinnouchi Yuko, Yoshida Yumiko, Matsuura Tetsuro, Narama Isao, Motomiya Yoshihiro, Takeuchi Masayoshi, Inoue Hiroyoshi, Yoshimura Akihiko, Bucala Richard, Imaizumi Tsutomu
Department of Internal Medicine III, Kurume University School of Medicine, Kurume 830-0011, Japan.
J Biol Chem. 2006 Jul 21;281(29):20213-20. doi: 10.1074/jbc.M602110200. Epub 2006 May 17.
Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis, suggesting that loss of PEDF contributes to proliferative diabetic retinopathy. However, the role of PEDF against retinal vascular hyperpermeability remains to be elucidated. We investigated here whether and how PEDF could inhibit the advanced glycation end product (AGE) signaling to vascular hyperpermeability. Intravenous administration of AGEs to normal rats not only increased retinal vascular permeability by stimulating vascular endothelial growth factor (VEGF) expression but also decreased retinal PEDF levels. Simultaneous treatments with PEDF inhibited the AGE-elicited VEGF-mediated permeability by down-regulating mRNA levels of p22(phox) and gp91(phox), membrane components of NADPH oxidase, and subsequently decreasing retinal levels of an oxidative stress marker, 8-hydroxydeoxyguanosine. PEDF also inhibited the AGE-induced vascular hyperpermeability evaluated by transendothelial electrical resistance by suppressing VEGF expression. Furthermore, PEDF decreased reactive oxygen species (ROS) generation in AGE-exposed endothelial cells by suppressing NADPH oxidase activity via down-regulation of mRNA levels of p22(PHOX) and gp91(PHOX). This led to blockade of the AGE-elicited Ras activation and NF-kappaB-dependent VEGF gene induction in endothelial cells. These results indicate that the central mechanism for PEDF inhibition of the AGE signaling to vascular permeability is by suppression of NADPH oxidase-mediated ROS generation and subsequent VEGF expression. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy.
色素上皮衍生因子（PEDF）是最有效的血管生成抑制剂，这表明PEDF的缺失会导致增殖性糖尿病视网膜病变。然而，PEDF在对抗视网膜血管高通透性方面的作用仍有待阐明。我们在此研究了PEDF是否以及如何抑制晚期糖基化终末产物（AGE）向血管高通透性的信号传导。给正常大鼠静脉注射AGEs不仅通过刺激血管内皮生长因子（VEGF）表达增加视网膜血管通透性，还降低视网膜PEDF水平。同时用PEDF处理可通过下调NADPH氧化酶的膜成分p22（phox）和gp91（phox）的mRNA水平，抑制AGE诱导的VEGF介导的通透性，随后降低视网膜氧化应激标志物8-羟基脱氧鸟苷的水平。PEDF还通过抑制VEGF表达，抑制了经内皮电阻评估的AGE诱导的血管高通透性。此外，PEDF通过下调p22（PHOX）和gp91（PHOX）的mRNA水平抑制NADPH氧化酶活性，从而减少AGE暴露的内皮细胞中活性氧（ROS）的产生。这导致内皮细胞中AGE诱导的Ras激活和NF-κB依赖性VEGF基因诱导的阻断。这些结果表明，PEDF抑制AGE向血管通透性信号传导的核心机制是抑制NADPH氧化酶介导的ROS产生及随后的VEGF表达。补充PEDF可能为阻止糖尿病视网膜病变的发展提供一种有前景策略。
