Document Detail

Copper chelation by tetrathiomolybdate inhibits lipopolysaccharide-induced inflammatory responses in vivo.
MedLine Citation:
PMID:  21724870     Owner:  NLM     Status:  MEDLINE    
Redox-active transition metal ions, such as iron and copper, may play an important role in vascular inflammation, which is an etiologic factor in atherosclerotic vascular diseases. In this study, we investigated whether tetrathiomolybdate (TTM), a highly specific copper chelator, can act as an anti-inflammatory agent, preventing lipopolysaccharide (LPS)-induced inflammatory responses in vivo. Female C57BL/6N mice were daily gavaged with TTM (30 mg/kg body wt) or vehicle control. After 3 wk, animals were injected intraperitoneally with 50 μg LPS or saline buffer and killed 3 h later. Treatment with TTM reduced serum ceruloplasmin activity by 43%, a surrogate marker of bioavailable copper, in the absence of detectable hepatotoxicity. The concentrations of both copper and molybdenum increased in various tissues, whereas the copper-to-molybdenum ratio decreased, consistent with reduced copper bioavailability. TTM treatment did not have a significant effect on superoxide dismutase activity in heart and liver. Furthermore, TTM significantly inhibited LPS-induced inflammatory gene transcription in aorta and heart, including vascular and intercellular adhesion molecule-1 (VCAM-1 and ICAM-1, respectively), monocyte chemotactic protein-1 (MCP-1), interleukin-6, and tumor necrosis factor (TNF)-α (ANOVA, P < 0.05); consistently, protein levels of VCAM-1, ICAM-1, and MCP-1 in heart were also significantly lower in TTM-treated animals. Similar inhibitory effects of TTM were observed on activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) in heart and lungs. Finally, TTM significantly inhibited LPS-induced increases of serum levels of soluble ICAM-1, MCP-1, and TNF-α (ANOVA, P < 0.05). These data indicate that copper chelation with TTM inhibits LPS-induced inflammatory responses in aorta and other tissues of mice, most likely by inhibiting activation of the redox-sensitive transcription factors, NF-κB and AP-1. Therefore, copper appears to play an important role in vascular inflammation, and TTM may have value as an anti-inflammatory or anti-atherogenic agent.
Hao Wei; Balz Frei; Joseph S Beckman; Wei-Jian Zhang
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-07-01
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  301     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-31     Completed Date:  2011-11-01     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H712-20     Citation Subset:  IM    
Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA.
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MeSH Terms
Analysis of Variance
Anti-Inflammatory Agents / pharmacology*
Ceruloplasmin / metabolism
Chelating Agents / pharmacology*
Chemokine CCL2 / genetics,  metabolism
Copper / metabolism*
Disease Models, Animal
Gene Expression Regulation / drug effects
Inflammation / chemically induced,  genetics,  metabolism,  prevention & control*
Inflammation Mediators / metabolism
Intercellular Adhesion Molecule-1 / genetics,  metabolism
Mice, Inbred C57BL
Molybdenum / pharmacology*
NF-kappa B / metabolism
RNA, Messenger / metabolism
Superoxide Dismutase / metabolism
Transcription Factor AP-1 / metabolism
Tumor Necrosis Factor-alpha / genetics,  metabolism
Vascular Cell Adhesion Molecule-1 / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Ccl2 protein, mouse; 0/Chelating Agents; 0/Chemokine CCL2; 0/Inflammation Mediators; 0/Lipopolysaccharides; 0/NF-kappa B; 0/RNA, Messenger; 0/Transcription Factor AP-1; 0/Tumor Necrosis Factor-alpha; 0/Vascular Cell Adhesion Molecule-1; 0/lipopolysaccharide, E coli O55-B5; 126547-89-5/Intercellular Adhesion Molecule-1; 7439-98-7/Molybdenum; 7440-50-8/Copper; 91U3TGV99T/tetrathiomolybdate; EC Dismutase; EC

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