Pigment Epithelium-derived Factor Inhibits Advanced Glycation End Product-induced Retinal Vascular Hyperpermeability by Blocking Reactive Oxygen Species-mediated Vascular Endothelial Growth Factor Expression

Abstract

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-B-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 oxidasemediated ROS generation and subsequent VEGF expression. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy.

Vascular endothelial growth factor in eye disease

“…Parallel actions of high glucose and oxidative stress might inhibit the production of proteins that normally inhibit VEGF expression, enhancing this autocrine process. This hypothesis is supported by studies showing that decreased levels of endostatin and PEDF are correlated with increased VEGF levels in patients with diabetic retinopathy (Boehm et al, 2003;Funatsu et al, 2003) and that treatment with endostatin or PEDF can reduce VEGF-or AGE-induced retinal vascular permeability in vivo Yamagishi et al, 2006).…”

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

“…once daily in our model because we have previously found that (1) intravenous administration of 3.3 to 10 g PEDF/100 g b.wt. once a day exerts antithrombogenic, antipermeability, and anti-inflammatory effects in rats 16,23,24,29 ; (2) the peak concentration of circulating PEDF level is obtained at 2 hours after the 10 g PEDF injection/100 g b.wt. ; and (3) its level is increased to about 2-fold of basal level (from about 200 ng/ml to 400 ng/ml) in SD rats at 8 weeks of age.…”

DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice

“…28,29 Furthermore, VEGF not only has a crucial role in tumor angiogenesis and expansion but it could also evoke inflammatory reactions in tumors. [30][31][32][33][34][35] As we have previously shown that VEGF is induced by engagement of RAGE with AGE, 24,26 we studied the effects of AGE-aptamer on angiogenesis and macrophage infiltration in G361 melanoma and then investigated the involvement of AGE-RAGE-VEGF axis in anti-tumor actions of aptamer. For this, we first examined the effects of AGE-aptamer on expression levels of CD31 and Mac-3, markers of capillary endothelial cells and macrophages, respectively.…”

“…24 In brief, BSA (25 mg/ml) was incubated under sterile conditions with 0.1 M glyceraldehyde in 0.2 M NaPO 4 buffer (pH 7.4) for 7 days. Then unincorporated sugars were removed by PD-10 column chromatography and dialysis against phosphate-buffered saline.…”