Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Sarah X Zhang, Joshua J Wang, Azar Dashti, Kenneth Wilson, Ming-Hui Zou, Luke Szweda, Jian-Xing Ma, Timothy J Lyons

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

Oxidized and/or glycated low-density lipoprotein (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 microg/ml 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-kappaB (NF-kappaB) 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-kappaB activation, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockade of NF-kappaB 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 superoxide dismutase 1 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.
Original languageEnglish
Pages (from-to)135-43
Number of pages9
JournalJournal of Molecular Endocrinology
Volume41
Issue number3
DOIs
Publication statusPublished - Sep 2008

Keywords

  • Cell Nucleus
  • Cells, Cultured
  • Chemokine CCL2
  • Eye Proteins
  • Humans
  • Inflammation
  • Lipoproteins, LDL
  • NF-kappa B
  • Nerve Growth Factors
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Oxidative Stress
  • Pericytes
  • Peroxynitrous Acid
  • Protein Transport
  • Reactive Oxygen Species
  • Retina
  • Serpins
  • Superoxide Dismutase
  • Up-Regulation

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