Abstract
Previous results indicated that intravenous injection of copper in the form of a copper-histidine complex in rats triggers the transcriptional induction of the inducible form of nitric oxide synthase (NOS-II). Here, the authors demonstrate that copper activates the transcription factor NF-kappaB in the liver and lung tissues of rats, and that this effect is mediated by oxidative stress, since all copper-induced changes, which include histological alterations, formation of nitrotyrosines, vascular pressure drop, production of tumor necrosis factor-alpha (TNF-alpha), induction of NOS-II and nitrites, are readily prevented by pretreatment of the animals with the antioxidant tempol. By using electrophoretic mobility shift assays, the p50/p65 dimer and higher molecular weight aggregates have been found to be involved in the copper-induced NF-kappaB activation. COX-2, a NF-kappaBdependent gene involved in the inflammatory response, was also transcriptionally induced by copper, this effect being reduced in the presence of tempol. These results suggest that a physiopathological status, characterized by hypercupremic situations, may lead to the onset of inflammation through production of ROS and activation of NF-kappaB.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antioxidants / pharmacology
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Blood Pressure / drug effects
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Copper / administration & dosage
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Copper / pharmacology*
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Cyclic N-Oxides / pharmacology
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Cyclooxygenase 2 / genetics
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Gene Expression / drug effects
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Histidine / analogs & derivatives
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Histidine / pharmacology
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Liver / metabolism
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Liver / pathology
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Lung / metabolism
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Lung / pathology
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Male
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NF-kappa B / metabolism*
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NF-kappa B p50 Subunit / metabolism
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Nitrates / blood
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Nitric Oxide Synthase Type II / metabolism
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Nitrites / blood
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Organometallic Compounds / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects*
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Spin Labels
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Transcription Factor RelA / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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Tyrosine / analogs & derivatives
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Tyrosine / metabolism
Substances
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Antioxidants
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Cyclic N-Oxides
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NF-kappa B
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NF-kappa B p50 Subunit
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Nitrates
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Nitrites
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Organometallic Compounds
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RNA, Messenger
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Spin Labels
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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3-nitrotyrosine
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Tyrosine
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Histidine
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Copper
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copper histidine
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Nitric Oxide Synthase Type II
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Cyclooxygenase 2
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Ptgs2 protein, rat
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tempol