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.

Treatment with a copper-selective chelator causes substantive improvement in cardiac function of diabetic rats with left-ventricular impairment

“…In a recent study, TTM reportedly inhibited vascular inflammation and atherosclerotic lesion development in apolipoprotein-E deficient mice [47], raising the possibility that similar effects could also contribute to the cardiovascular responses to trientine. However, in this study, 10-weeks treatment with TTM induced significant lowering of circulating ceruloplasmin levels, raising the possibility that the reported findings could have been confounded by concomitant copper deficiency, as signaled by marked lowering of serum ceruloplasmin levels.…”

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

“…Cardiac endothelial dysfunction observed in ApoE -/- (apolipoprotein E) knockout mice, prone to atherosclerosis, have been studied after the oral administration of TM for 10 weeks [270]. A specific reduction of bioavailable copper has been detected in both the serum (in the holo-ceruloplasmin form) and aorta, associated with a moderate decrease of both atherosclerotic lesions and accumulating macrophages [270].…”

“…Cardiac endothelial dysfunction observed in ApoE -/- (apolipoprotein E) knockout mice, prone to atherosclerosis, have been studied after the oral administration of TM for 10 weeks [270]. A specific reduction of bioavailable copper has been detected in both the serum (in the holo-ceruloplasmin form) and aorta, associated with a moderate decrease of both atherosclerotic lesions and accumulating macrophages [270]. Specifically, TM-induced copper starvation in TNFα-treated human aortic endothelial cells has been shown to trigger the inactivation of NFκB and AP-1 pathways and reduced expression of ICAM1 and vascular cell adhesion molecule 1 [259].…”

Copper Induces Vasorelaxation and Antagonizes Noradrenaline -Induced Vasoconstriction in Rat Mesenteric Artery

“…Copper is involved in critical processes including mitochondrial respiration and antioxidant capacity in the body [1]. Cellular copper levels must be tightly controlled because both copper accumulation and deficiency can induce cardiovascular disorders [2,3,4]. Many lines of evidences showed that high serum copper was associated with increased cardiovascular risks, for example, copper level of ischemic cardiomyopathy patients was higher than that of the healthy volunteers [5]; serum copper concentration was higher in rheumatic heart disease patients than in controls [6]; Serum copper level in subjects with acute decompensation of chronic heart failure was higher than that with chronic stable heart failure and serum copper was as a marker of inflammation in prediction of short term outcome in high risk patients with chronic heart failure [7].…”