title: Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice.
abstract: Endothelial activation, which is characterized by upregulation of cellular adhesion molecules and pro-inflammatory chemokines and cytokines, and consequent monocyte recruitment to the arterial intima are etiologic factors in atherosclerosis. Redox-active transition metal ions, such as copper and iron, may play an important role in endothelial activation by stimulating redox-sensitive cell signaling pathways. We have shown previously that copper chelation by tetrathiomolybdate (TTM) inhibits LPS-induced acute inflammatory responses in vivo. Here, we investigated whether TTM can inhibit atherosclerotic lesion development in apolipoprotein E-deficient (apoE-/-) mice. We found that 10-week treatment of apoE-/- mice with TTM (33-66 ppm in the diet) reduced serum levels of the copper-containing protein, ceruloplasmin, by 47%, and serum iron by 26%. Tissue levels of "bioavailable" copper, assessed by the copper-to-molybdenum ratio, decreased by 80% in aorta and heart, whereas iron levels of these tissues were not affected by TTM treatment. Furthermore, TTM significantly attenuated atherosclerotic lesion development in whole aorta by 25% and descending aorta by 45% compared to non-TTM treated apoE-/- mice. This anti-atherogenic effect of TTM was accompanied by several anti-inflammatory effects, i.e., significantly decreased serum levels of soluble vascular cell and intercellular adhesion molecules (VCAM-1 and ICAM-1); reduced aortic gene expression of VCAM-1, ICAM-1, monocyte chemotactic protein-1, and pro-inflammatory cytokines; and significantly less aortic accumulation of M1 type macrophages. In contrast, serum levels of oxidized LDL were not reduced by TTM. These data indicate that TTM inhibits atherosclerosis in apoE-/- mice by reducing bioavailable copper and vascular inflammation, not by altering iron homeostasis or reducing oxidative stress.
authors: Linus Pauling Institute and Department of Biochemistry & Biophysics, Oregon State University, Corvallis, OR 97331, USA.
authors: Hao
authors: H
authors: Wei
authors: Wei-Jian
authors: WJ
authors: Zhang
authors: Timothy S
authors: TS
authors: McMillen
authors: Renee C
authors: RC
authors: Leboeuf
authors: Balz
authors: B
authors: Frei
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002570:Ceruloplasmin / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007501:Iron / Q000097:blood; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008982:Molybdenum / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D002614:Chelating Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008055:Lipids; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D007501:Iron; D002570:Ceruloplasmin