期刊
JOURNAL OF MOLECULAR ENDOCRINOLOGY
卷 41, 期 3-4, 页码 135-143出版社
BIOSCIENTIFICA LTD
DOI: 10.1677/JME-08-0011
关键词
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资金
- NIH [P20RR024215]
- JDRF [5-2007-793, 18-2007-860]
- OCAST
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR024215] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R01EY012231] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL080499, R01HL105157, R01HL110488, R01HL079584, R01HL074399, R01HL096032, R01HL089920] Funding Source: NIH RePORTER
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 mu g/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-kappa B (NF-kappa 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-kappa B activation, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockade of NF-kappa 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 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.
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