Circulation Research, 2004-10, Vol.95 (8), p.780-788
2004
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- Autor(en) / Beteiligte
- Titel
- Role for Sterol Regulatory Element-Binding Protein in Activation of Endothelial Cells by Phospholipid Oxidation Products
- Ist Teil von
- Circulation Research, 2004-10, Vol.95 (8), p.780-788
- Ort / Verlag
- Hagerstown, MD: American Heart Association, Inc
- Erscheinungsjahr
- 2004
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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-β-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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0009-7330eISSN: 1524-4571, 1524-4539DOI: 10.1161/01.RES.0000146030.53089.18Titel-ID: cdi_proquest_miscellaneous_66978833
- Format
- –
- Schlagworte
- Animals, Aorta, Arteriosclerosis - metabolism, Arteriosclerosis - pathology, beta-Cyclodextrins - pharmacology, Biological and medical sciences, Cattle, Caveolin 1, Caveolins - genetics, Caveolins - metabolism, CCAAT-Enhancer-Binding Proteins - genetics, CCAAT-Enhancer-Binding Proteins - physiology, Cell Compartmentation, Cell Membrane - metabolism, Cell Nucleus - chemistry, Cells, Cultured, Cholesterol - metabolism, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, DNA-Binding Proteins - physiology, Endoplasmic Reticulum - metabolism, Endothelial Cells - metabolism, Endothelium, Vascular - cytology, Fundamental and applied biological sciences. Psychology, Golgi Apparatus - metabolism, HeLa Cells - metabolism, Humans, Hydroxycholesterols - pharmacology, Inflammation - metabolism, Interleukin-8 - biosynthesis, Interleukin-8 - genetics, Intracellular Signaling Peptides and Proteins, Membrane Lipids - metabolism, Membrane Proteins - genetics, Membrane Proteins - metabolism, Phosphatidylcholines - pharmacology, Phospholipid Ethers - pharmacology, Recombinant Fusion Proteins - metabolism, STAT3 Transcription Factor, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Trans-Activators - metabolism, Transcription Factors - genetics, Transcription Factors - physiology, Transcription, Genetic - drug effects, Transfection, Vertebrates: cardiovascular system