Copper deficiency and cardiovascular disease: role of peroxidation, glycation, and nitration

Abstract

Dietary copper deficiency causes a variety of cardiovascular deficits. Systemic effects include high blood pressure, enhancement of inflammation, anemia, reduced blood clotting, and possibly arteriosclerosis. Effects on specific organs or tissues include weakened structural integrity of the heart and blood vessels, impairment of energy use by the heart, reduced ability of the heart to contract, altered ability of blood vessels to control their diameter and grow, and altered structure and function of circulating blood cells. In some instances, the cause of a defect can be directly attributed to reduced activity of a specific copper-dependent enzyme. However, three nonspecific mechanisms of damage have been implicated in cardiovascular defects of copper deficiency. They are peroxidation, the interaction of oxygen-derived free radicals with lipids and proteins (possibly DNA); glycation, the nonenzymatic glycosylation of proteins; and nitration, the interaction of nitric oxide and its metabolites with peptides and proteins. Though independently these mechanisms present great potential for damage, the possibility that they may interact presents an added reason for concern. Furthermore, the fact that at least two of these mechanisms are associated with diabetes and aging suggests that copper deficiency may exacerbate deficits associated with these two conditions.

Cyclooxygenase-2 is Upregulated in Copper-Deficient Rats

“…Support for the view that copper deficiency causes peroxidative damage has been reviewed [18]. The primary observations that support the presence of oxidative stress in copper deficiency are the reduction in activities of several copper-dependent antioxidant enzymes, superoxide dismutase, ceruloplasmin and cytochrome c oxidase, and possibly non-copper-dependent enzymes such as catalase [19,20] These findings have been complemented by observations of increased peroxidative products in blood, tissues and exhaled breath [21][22][23] by increased susceptibility to oxidative damage in copperdeficient animals [24] by correlation of severity of the defects with extent of peroxidation [25] and by amelioration of defects by treatment with antioxidants [26] or by transgenically elevating oxidant status [27].…”

Copper, oxidative stress, and human health

“…The redox cycling ability of Cu enables it to play an important role in electron transfer reactions. A deficit of Cu can result in impaired energy production, abnormal glucose and cholesterol metabolism, increased oxidative damage, increased tissue iron (Fe) accrual, altered structure and function of circulating blood and immune cells, abnormal neuropeptide synthesis and processing, aberrant cardiac electrophysiology, impaired myocardial contractility, and persistent effects on neurobehavior and the immune system (Harris, 2003;Keen et al, 2003b;Saari, 2000). Several human disorders with genetic mutations in Cu transporters have further defined the role of Cu in human health.…”

Diabetes and dietary copper alter 67Cu metabolism and oxidant defense in the rat

“…Increased oxidative damage to protein, lipid and DNA has been observed and implicated in the pathogenesis of diabetic complications [14,15,[19][20][21]. Indeed, similar mechanisms of pathogenesis including increased glycation, peroxidation and nitration have been reported for both diabetes and Cu deficiency [22]. Given the above, we used 67 Cu to aid in determining short-term Cu distribution in normal and diabetic rats.…”