Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein.
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.
Zhang
Sarah X
SX
Department of Medicine Endocrinology, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, 331A, Oklahoma City, Oklahoma 73104, USA.
Wang
Joshua J
JJ
Dashti
Azar
A
Wilson
Kenneth
K
Zou
Ming-Hui
MH
Szweda
Luke
L
Ma
Jian-Xing
JX
Lyons
Timothy J
TJ
D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005136:Eye Proteins / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D020286:Pericytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D030421:Peroxynitrous Acid / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000201:enzymology; D015843:Serpins / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000099174:Pigment Epithelium-Derived Factor
D018932:Chemokine CCL2; D005136:Eye Proteins; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D009414:Nerve Growth Factors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid; D017382:Reactive Oxygen Species; D015843:Serpins; D013482:Superoxide Dismutase; D000099174:Pigment Epithelium-Derived Factor; C099252:oxidized low density lipoprotein