Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice

• Published in: Atherosclerosis 2012-08, Vol.223 (2), p.306-313
• Main Authors: Wei, Hao, Zhang, Wei-Jian, McMillen, Timothy S, LeBoeuf, Renee C, Frei, Balz
• Format: Article
• Language: English
• Subjects: adhesion; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; anti-inflammatory activity; Anti-Inflammatory Agents - pharmacology; aorta; Aorta - drug effects; Aorta - metabolism; Aortic Diseases - genetics; Aortic Diseases - immunology; Aortic Diseases - metabolism; Aortic Diseases - prevention & control; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - genetics; Atherosclerosis - immunology; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; blood serum; Cardiology. Vascular system; Cardiovascular; cell adhesion; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Ceruloplasmin - metabolism; Chelating Agents - pharmacology; chelation; chemokines; copper; Copper - metabolism; Copper chelation; Cytokines - genetics; Cytokines - metabolism; diet; Disease Models, Animal; Emergency and intensive care: renal failure. Dialysis management; Endothelial activation; Female; ferroxidase; gene expression; heart; homeostasis; inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Inflammation - prevention & control; Inflammation Mediators - metabolism; Intensive care medicine; iron; Iron - blood; Lipids - blood; Liver - drug effects; Liver - metabolism; low density lipoprotein; macrophages; Medical sciences; metal ions; Mice; Mice, Inbred C57BL; Mice, Knockout; Molybdenum - pharmacology; Myocardium - metabolism; oxidative stress; recruitment; signal transduction; Tetrathiomolybdate; Vascular inflammation
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2012.06.013

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.