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Macrophage-specific inhibition of NF-κB activation reduces foam-cell formation
| article |
2007
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| Author: |
Ferreira, V.
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Dijk, K.W. van
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Groen, A.K.
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Vos, R.M.
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Kaa, J. van der
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Gijbels, M.J.J.
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Havekes, L.M.
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Pannekoek, H.
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| Keywords: |
Biology · Biomedical Research · ABCA1 mediated cholesterol efflux · Foam cell formation · Macrophage specific inhibition of NF-κB, IκBα · ox-LDL-PPARγ-CD36 "feed-forward cycle" · I kappa B kinase alpha · immunoglobulin enhancer binding protein · article · cell differentiation · cell line · cell specificity · controlled study · cytoplasm · foam cell · gene expression · human · human cell · lipid oxidation · lipid transport · monocyte · mouse · nonhuman · peritoneum cell · priority journal · protein degradation · protein expression · transgenic mouse · Animals · Antigens, CD36 · ATP-Binding Cassette Transporters · Cell Line · DNA-Binding Proteins · Foam Cells · Humans · I-kappa B Proteins · Lipoproteins, LDL · Macrophages · Mice · Mice, Inbred C57BL · NF-kappa B · PPAR gamma · Receptors, Cytoplasmic and Nuclear · Scavenger Receptors, Class A
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Accumulation of lipid-laden macrophages is a hallmark of atherosclerosis. The relevance of the key transcription factor nuclear factor κB (NF-κB) for macrophage-derived foam-cell formation has not been unequivocally resolved. Transgenic mice lines were generated in which NF-κB activation is specifically inhibited in macrophages by overexpressing a trans-dominant, non-degradable form of IκBα (IκBα (32A/36A)) under control of the macrophage-specific SR-A promoter. Alanine substitution of serines 32 and 36 prevents degradation and retains the inactive NF-κB/IκBα (32A/36A) complex in the cytoplasm. Similarly, stable human THP1 monocytic cell lines were generated with integrated copies of IκBα (32A/36A) cDNA. Upon treatment with oxidized low-density lipoprotein (ox-LDL), murine peritoneal macrophages from transgenic IκBα (32A/36A) mice, as well as THP1/IκBα (32A/36A) clones, display decreased lipid loading after differentiation into macrophages. This is accompanied by increased expression of the transcription factors PPARγ and LXRα as well as of the major cholesterol-efflux transporter ABCA1. Paradoxically, mRNA expression of the 'lipid-uptake' receptor CD36 is also increased. Since the net result of these changes is reduction of foam-cell formation, it is proposed that under specific inhibition of NF-κB activation, ABCA1-mediated cholesterol efflux prevails over CD36-mediated lipid influx. © 2006 Elsevier Ireland Ltd. All rights reserved.
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[Abstract]
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