TitleCopper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice.
Publication TypeJournal Article
Year of Publication2012
AuthorsWei H, Zhang W-J, McMillen TS, Leboeuf RC, Frei B
Date Published2012 Aug
KeywordsAnimals, Anti-Inflammatory Agents, Aorta, Aortic Diseases, Apolipoproteins E, Atherosclerosis, Biomarkers, Cell Adhesion Molecules, Ceruloplasmin, Chelating Agents, Copper, Cytokines, Disease Models, Animal, Female, Inflammation, Inflammation Mediators, Iron, Lipids, Liver, Mice, Mice, Inbred C57BL, Mice, Knockout, Molybdenum, Myocardium

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.

Alternate JournalAtherosclerosis
PubMed ID22770994
PubMed Central IDPMC3417757
Grant ListR01 HL055362 / HL / NHLBI NIH HHS / United States
/ / Intramural NIH HHS / United States
R01 HL098227 / HL / NHLBI NIH HHS / United States
P01 AT002034 / AT / NCCIH NIH HHS / United States
P30 DK017047 / DK / NIDDK NIH HHS / United States