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This Article Accepted manuscript (PDF) All Versions of this Article: JME-08-0011v1 41/3/135    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, S. Articles by Ma, J.-X. Search for Related Content PubMed PubMed Citation Articles by Zhang, S. Articles by Ma, J.-X.

S Zhang, Medicine, Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, United States
J Wang, OKLAHOMA CITY, United States
A Dashti, OKLAHOMA CITY, United States
K Wilson, OKLAHOMA CITY, United States
L Szweda, Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, OKLAHOMA CITY, United States
M Zou, OKLAHOMA CITY, United States
T Lyons, OKLAHOMA CITY, United States
J Ma, OKLAHOMA CITY, United States

Correspondence: Sarah Zhang, Email: xin-zhang{at}ouhsc.edu

Abstract

Oxidized and/or glycated LDL may mediate capillary injury in diabetic retinopathy. The mechanisms may involve pro-inflammatory and pro-oxidant effects on retinal capillary pericytes. In this study, these effects, and the protective effects of pigment epithelium-derived factor (PEDF), were defined in a primary human pericyte model. Human retinal pericytes were exposed to 100 µg/ml of native LDL (N-LDL) or heavily oxidized glycated LDL (HOG-LDL) with or without PEDF at 10-160 nM for 24 h. To assess pro-inflammatory effects, monocyte chemoattractant protein-1 (MCP-1) secretion was measured by ELISA, and nuclear factor kappa B (NF-B) activation was detected by immunocytochemistry. Oxidative stress was determined by measuring intracellular reactive oxygen species (ROS), peroxynitrite (ONOO-) formation, inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. The results showed that MCP-1 was significantly increased by HOG-LDL, and the effect was attenuated by PEDF in a dose-dependent manner. PEDF also attenuated the HOG-LDL-induced NF-B activation, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockade of NF-B activation. Further studies demonstrated that HOG-LDL, but not N-LDL, significantly increased ONOO- formation, NO production, and iNOS expression. These changes were also alleviated by PEDF. Moreover, PEDF significantly ameliorated HOG-LDL-induced ROS generation through up-regulation of SOD1 expression. Taken together, these results demonstrate pro-inflammatory and pro-oxidant effects of HOG-LDL on retinal pericytes, which were effectively ameliorated by PEDF. Suppressing MCP-1 production and thus inhibiting macrophage recruitment may represent a new mechanism for the salutary effect of PEDF in diabetic retinopathy and warrants more studies in future.