Abstract:
:Oxidized phospholipids, including oxidation products of palmitoyl-arachidonyl-phosphatidyl choline (PAPC), are mediators of inflammation in endothelial cells (ECs) and known to induce several chemokines, including interleukin-8 (IL-8). In this study, we show that oxidized PAPC (OxPAPC), which accumulates in atherosclerotic lesions, paradoxically depletes endothelial cholesterol, causing caveolin-1 internalization from the plasma membrane to the endoplasmic reticulum and Golgi, and activates sterol regulatory element-binding protein (SREBP). Cholesterol loading reversed these effects. SREBP activation resulted in increased transcription of the low-density lipoprotein receptor, a target gene of SREBP. We also provide evidence that cholesterol depletion and SREBP activation are signals for OxPAPC induction of IL-8. Cholesterol depletion by methyl-beta-cyclodextrin induced IL-8 synthesis in a dose-dependent manner. Furthermore, cholesterol loading of ECs by either the cholesterol-cyclodextrin complex or caveolin-1 overexpression inhibited OxPAPC induction of IL-8. These observations suggest that changes in cholesterol level can modulate IL-8 synthesis in ECs. The OxPAPC induction of IL-8 was mediated through the increased binding of SREBP to the IL-8 promoter region, as revealed by mobility shift assays. Overexpression of either dominant-negative SREBP cleavage-activating protein or 25-hydroxycholesterol significantly suppressed the effect of OxPAPC on IL-8 transcription. A role for SREBP activation in atherosclerosis is suggested by the observation that EC nuclei showed strong SREBP staining in human atherosclerotic lesions. The current studies suggest a novel role for endothelial cholesterol depletion and subsequent SREBP activation in inflammatory processes in which phospholipid oxidation products accumulate.
journal_name
Circ Resjournal_title
Circulation researchauthors
Yeh M,Cole AL,Choi J,Liu Y,Tulchinsky D,Qiao JH,Fishbein MC,Dooley AN,Hovnanian T,Mouilleseaux K,Vora DK,Yang WP,Gargalovic P,Kirchgessner T,Shyy JY,Berliner JAdoi
10.1161/01.RES.0000146030.53089.18subject
Has Abstractpub_date
2004-10-15 00:00:00pages
780-8issue
8eissn
0009-7330issn
1524-4571pii
01.RES.0000146030.53089.18journal_volume
95pub_type
杂志文章abstract::Vascular smooth muscle cells (VSMCs) proliferate in response to arterial injury. Recent findings suggest that, in addition to platelet-derived growth factors, growth factors from inflammatory cells and endothelial cells at the site of injury may contribute to VSMC proliferation. We hypothesized that a common mechanism...
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更新日期:2001-05-25 00:00:00
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更新日期:2007-04-13 00:00:00
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更新日期:2006-11-24 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2000-07-21 00:00:00
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pub_type: 杂志文章,收录出版
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更新日期:1978-11-01 00:00:00
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更新日期:1977-08-01 00:00:00
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doi:10.1161/CIRCRESAHA.111.240655
更新日期:2011-04-01 00:00:00
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更新日期:2006-04-14 00:00:00
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更新日期:2003-11-28 00:00:00
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更新日期:2014-02-28 00:00:00
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abstract::This study examines the cellular basis and specificity of the effects of adenosine on early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and triggered activity (TA) induced by various drugs with different mechanisms of action. Membrane potential and currents were measured in isolated guinea pig ve...
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doi:10.1161/01.res.70.4.743
更新日期:1992-04-01 00:00:00
abstract::Cyclic GMP modulates gene expression in vascular smooth muscle cells (SMCs) in part by stimulating cGMP-dependent protein kinase I (PKGI) and the phosphorylation of transcription factors. In some cells, cGMP increases nuclear translocation of PKGI and PKGI-dependent phosphorylation of transcription regulators; however...
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更新日期:2008-07-03 00:00:00