Copper induces--and copper chelation by tetrathiomolybdate inhibits--endothelial activation in vitro.
Endothelial activation with increased expression of cellular adhesion molecules and chemokines critically contributes to vascular inflammation and atherogenesis. Redox-active transition metal ions play an important role in vascular oxidative stress and inflammation. Therefore, the goal of the present study was to investigate the role of copper in endothelial activation and the potential anti-inflammatory effects of copper chelation by tetrathiomolybdate (TTM) in human aortic endothelial cells (HAECs). Incubating HAECs with cupric sulfate dose- and time-dependently increased mRNA and protein expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1). Copper also activated the redox-sensitive transcription factors, nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1), which was inhibited by pretreatment of the cells with TTM. Furthermore, TTM dose-dependently inhibited tumor necrosis factor α (TNFα)-induced activation of NF-κB and AP-1, as well as mRNA and protein expression of VCAM-1, ICAM-1, and MCP-1, which was abolished by preincubating the cells with 5 µM TTM and 15 µM cupric sulfate. The inhibitory effect of TTM on TNFα-induced NF-κB activation was associated with decreased phosphorylation and degradation of IκBα. These data suggest that intracellular copper causes activation of redox-sensitive transcription factors and upregulation of inflammatory mediators in endothelial cells. Copper chelation by TTM may attenuate TNFα-induced endothelial activation and, hence, inhibit vascular inflammation and atherosclerosis.
Hao
H
Wei
Wei-Jian
WJ
Zhang
Renee
R
Leboeuf
Balz
B
Frei
D001011:Aorta; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology*; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D003300:Copper; D019327:Copper Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics; D008982:Molybdenum / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
D015815:Cell Adhesion Molecules; D002614:Chelating Agents; D018925:Chemokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D019327:Copper Sulfate
AP-1; Endothelial activation; Metal chelation; NF-κB; Vascular inflammation