Cardiovascular Toxic Effects of Copper

Salus J Health Sci. 2016; 2(3): 28-36 DOI: https://dx.doi.org/10.5935/2447-7826.20160024

REVIEW ARTICLE

Cardiovascular toxic effects of copper

Karolini Zuqui Nunes 1, Mirian Fioresi 2

1 Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, ES, Brazil. 2 Department of Nursing, Federal University of Espírito Santo, Vitoria, ES, Brazil.

Article received on September 2, 2016 Article approved on October 3, 2016

Keywords Abstract Copper; Toxicity; Objective : To describe the main cardiovascular effects developed Cardiovascular by copper. Method : This is a narrative review of the literature. system Results : Copper can act as a cofactor for some enzymes that act on the cardiovascular system, having an important role in the development of atherogenesis in the angiogenic control and the development of cardiac hypertrophy. Conclusion : Both the deficiency and contamination with copper can lead to changes in the cardiovascular system. It is undeniable the need for further research that can clarify the effects and mechanisms involved in the changes produced by copper in the heart and blood vessels. However, it is essential that the safe values of the recommended daily intake to be set and define the blood concentrations of this metal to be reviewed.

*Corresponding author: [email protected]

plays an important role in human Introduction metabolism, mainly acting as a cofactor for the activity of several enzymes. 3 Among Copper (Cu) is an essential element these enzymes, we can highlight the necessary for the maintenance and cytochrome C oxidase, necessary for functioning of living organisms. 1 It is the aerobic metabolism; Lysyl oxidase, which third most abundant metal in the body 2 and participates in the synthesis of collagen and

28 Salus J Health Sci. 2016; 2(3): 28-36 elastin; Dopamine ß-hydroxylase, which age, type of food and amount of Cu in the plays an important role in the conversion of diet. It has been shown that copper dopamine to noradrenaline; and superoxide absorption is higher in women and children dismutase, an antioxidant enzyme that acts and that there are no differences between on the conversion of superoxide to young adults and older people. 12 After hydrogen peroxide. 4 intestinal absorption, 25% of copper Copper homeostasis is essential for remains in the circulation bound to albumin, enzymatic functioning and proper while the remainder is absorbed by the liver. functioning of the body. Metal deficiency After absorption into the liver, about 80% may lead to decreased activity of several of the copper is destined for the blood enzymes, resulting mainly in the circulation bound to ceruloplasmin, while 5 the remainder is re-excreted into the development of oxidative imbalance, 13 neurological alterations, 6 hepatic and gastrointestinal system. The half-life of 7-9 copper in a healthy individual is cardiovascular. In addition, although it is 14 an essential micronutrient for man, Cu is approximately 26 days and most of the excretion occurs via the bile duct. There is toxic at high levels. An overload of this no evidence that urinary excretion plays a metal easily activates Fenton reactions, controlling role in Cu homeostasis in resulting in oxidative cellular damage and response to changes in metal intake. 10 cell death. Cu toxicity as a result of dietary excess is generally not considered one of the Under normal physiological conditions, in most important sources of exposure to the which the concentration of copper in the metal, probably as a result of Cu 10 uptake body is normal, ATP7A is the enzyme and excretion control mechanisms. responsible for absorbing copper in the However, when copper homeostasis is intestine and transporting it to the metal- discontinued, pathological conditions can dependent enzymes. However, when total be developed. In addition to metabolic reserves of intracellular copper increase, changes, Cu toxicity may result from ATP7A moves to the cell membrane to 15 exposure to excess caused by accident, promote copper efflux. environmental contamination, the use of In the plasma membrane and in intracellular bactericidal and fungicidal agents based on vesicles, the CTR1 transporter plays a copper, and the emission of copper smelting fundamental role in the uptake of copper. industry. 10,11 In general, copper deficiency This transporter acts to control copper or toxicity from metabolic disturbances or uptake through cellular plasma membranes, exposure to metal may result in serious whereas extracellular copper elevations damage to the human body. Considering induce CTR1 endocytosis to vesicles that loss of copper homeostasis offersrisks whereas a decrease in extracellular copper to human health, this review seeks to restores CTR1 levels in the plasma describe the human exposure to copper and membrane. 16 After copper entry into the its main effects on the cardiovascular cell, it binds to cytosolic chaperones that system. then transfer the copper to specific cellular targets. 17

Copper homeostasis is essential for the - Copper metabolism functioning of the body. Changes in copper metabolism are characteristic of some Absorption of copper occurs mainly in the genetic diseases such as Menkes Disease proximal part of the small intestine, where and Wilson's Disease. Menkes disease is it is transported to the liver through the characterized by copper deficiency. The portal vein. Several parameters affect the main characteristic of Menkes Disease is dietary Cu absorption rate, including sex, the low activity of the copper-dependent

29 Salus J Health Sci. 2016; 2(3): 28-36 enzyme (ATPA7). Wilson's disease is The concentration of Cu in food varies characterized by the copper toxicity that according to local conditions. Most diets normally affects the severely hepatic and contain enough Cu (1-5 mg) to prevent a nervous systems. 18 In Wilson's disease, a deficiency and not enough to cause toxicity. compromise exists in biliary excretion of There is little information available on Cu copper leading to an accumulation of metal intake and adequacy in populations with in the liver. When hepatic storage capacity specific diets, such as vegetarians and is exceeded, cell death begins, with the vegans. However, it has been shown that release of copper in plasma resulting in daily Cu intake is 27% higher in vegetarian hemolysis and copper deposition in women than in omnivorous women. 10 extrahepatic tissues. 19

- Recommended daily intake and safe blood - Human exposure to copper concentration

In nature, copper emission occurs from Although copper is recognized as an natural sources such as dust carried by the essential element for the body's functioning, wind, volcanoes, forest fires and through the uncertainties remain over reference the release of copper mines. Cu is one of the values of daily intake for humans. The most important metals for commercial and Recommended Daily Intake in the United industrial application. It is used as a metal States and Canada is 0.9 mg/day, with a alloy for the manufacture of machines, in tolerable intake level of 10 mg/day for constructions, in the transport industries and adults aged 19 years or older. 27 military weapons. 20,21 In addition, it is an It has been demonstrated that the daily important component of white gold and intake of copper can interfere in the body other alloys used for costume jewelry, water balance. Daily intake doses below 0.8 dental products and cosmetics. It can also be mg/day may lead to net losses, while doses used as an additive in paints, plastics, above 2.4 mg/day may lead to water lubricants and metal coatings. In Africa it is retention. 10 traditionally used in medicinal practices. 22 Due to its high commercial and industrial The usual concentration of copper in human demand, copper-based products are plasma is between 0.3-2.1 µg/mL for the produced on a large scale and it is believed intake of 1.4 to 2.0 mg of copper/day. 28 that this production will expand in the Population studies have shown copper coming years. 23 concentrations in healthy individuals of approximately 1 µg/mL. 29,30 A study In addition to the use of copper in the performed with the Brazilian population industrial sectors mentioned above, it is also showed serum copper concentration of 0.8 widely used in bactericidal and fungicidal µg mL in men and 1.4 µg/mL in women. 30 products in many agricultural crops, which This difference between the sexes is consequently leads to contamination of expected, since it is well known that soils and food that are produced. 24,25 In women, especially those in the 20-60 age addition, copper may also be present in group, increased the absorption of copper. potable water and its concentration may Estrogens also directly influence the vary depending on domestic plumbing metabolism of copper, contributing to the systems and groundwater composition. An increase of plasma levels of this metal. The increase in the acidity of the water may lead effects of estrogens on copper levels are to corrosion in copper plating and increase also more evident in pregnant women, as the concentration of the metal in the water. 26 they tend to have even higher concentrations. 31

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- Effects of intoxication and deficiency on and immune function is poorly the human body documented. 10

In addition to the changes in the described As mentioned, copper is an essential metal systems, intoxication and copper deficiency and its intake in food is important. are also capable of triggering However, in addition to exposure related to cardiovascular changes. Experimental and food intake, the population is still exposed epidemiological studies have demonstrated to metal because of its occurrence in the a relationship between exposure to metal environment and its industrial use. Copper and the emergence of some diseases of the concentrations in the body are tightly cardiovascular system. Some of these controlled under physiological conditions relationships and their mechanisms will be so that their excess or deficiency is harmful described below. to the body. In inflammatory conditions, serum copper levels are increased and trigger oxidative stress responses that - Effects on the cardiovascular system activate inflammatory responses. Interestingly, changes in copper metabolism, oxidative stress and Several studies have shown that high copper concentrations are associated with the inflammation are commonly present in 34- several chronic diseases. 32 development of cardiovascular diseases. 37 Among these diseases, atherosclerotic Inhalation is one of the most important disease is one of the most important causes routes of copper intoxication. Therefore, of mortality in the world, 38 characterized by lung tissue toxicity is of great concern. In persistent vascular inflammation, 39 low vitro studies have indicated that Cu can density lipoprotein (LDL) oxidation and induce cytotoxicity, oxidative stress and free radical formation. In this context, genetic toxicity in cultured human lung copper (Cu) is an essential micronutrient for cells. Some studies have shown that the functioning of enzymes that catalyze intratracheal instillation of Cu induces oxidation reactions of LDL and have been oxidative stress, inflammation and implicated in atherogenesis through 23 neoplastic lesions in rats. mechanisms that involve the signaling 38,40 In addition to pulmonary manifestations, pathways of NF-kB activation. It has chronic copper toxicity has been known to been demonstrated that serum Cu cause hepatotoxicity and hepatic cirrhosis. concentration is higher in patients with As observed in Wilson's disease and in atherosclerosis, and increases with the 38 certain metal intoxication conditions, severity of the disease. In addition, it has increased copper concentration has been shown that copper chelation in apoE- contributed to the development of mice effectively inhibits the development of Alzheimer's disease. 33 atherosclerotic lesion and improves inflammation in the cardiovascular It has also been hypothesized that copper system. 40 accumulation may be related to cognitive decline and changes in the production of Copper seems to play an important role in humoral and cellular factors of the immune controlling the activity of the enzymes nitric system. 10 Cu-deficient animals show oxide synthase (NOS) and guanylate 41 reduced neutrophil and T cell populations, cyclase (GC). In addition to the decreased phagocyte and B 10 lymphocyte development of inflammatory reactions in 41 activity. The production of antibodies by the body and the control of vascular tone. splenocyte T cells is also reduced. In Copper increases the conversion rate of L- humans, the relationship between Cu intake arginine to L-citrulline, depending on the presence of extracellular calcium.

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Extracellular calcium concentration is a copper supplementation improves prerequisite for the activation of eNOS by hypertrophic cardiac disease conditions. 47 agonists. Thus, Cu can affect the In addition to participating in the control of intracellular mobilization of Ca and alter the vascular functioning, copper is also functioning of eNOS. 42 essential for cardiac functioning. It has been In addition to regulate the eNOS function, shown that Cu supplementation restores Cu is essential for the functioning of another chronic cardiac hypertrophy induced by important enzyme for the control of pressure overload. The pressure overload vascular tone, Cu / Zn superoxide dismutase generated by constriction of the ascending (SOD). 43 It regulates the activity of this aorta causes a decrease in Cu levels in the enzyme in order to control the heart along with the development of vasoconstriction caused by oxygen free hypertrophic cardiomyopathy. 48 Overload radicals. Since copper is a cofactor for the causes homocysteine buildup in the heart, functioning of SOD, increased which is accompanied by copper depletion concentrations of the metal could increase through the formation of copper- the enzymatic activity, while diminished homocysteine complexes and the excretion concentrations could lead to a decrease in of the complexes. Copper supplementation SOD activity and consequent increase in recovers cytochrome c oxidase activity and superoxide production. It has been promotes myocardial angiogenesis, along demonstrated in experimental studies that with regression of cardiac hypertrophy and copper could prevent the development of recovery of contractile function. 49 As peripheral vasospasm 44 and that incubation previously mentioned, Cu increases VEGF with submicromolar concentrations levels and promotes angiogenesis in of Cu impair endothelium-dependent hypertrophic hearts, improving the vasorelaxation probably because of the parameters of cardiac activity. 48 45 intracellular generation of O2. However, it is sometimes observed that, Copper is characterized as a required under chronic ischemic conditions, cofactor in all angiogenic signaling capillary density is decreased in the cascades, so much so that a metal deficiency heart. 50,51 Epidemiological studies have causes neovascularization to decrease. In demonstrated a relationship between copper addition, progression of various angiogenic deficiency and ischemic heart disease. The pathologies (eg, diabetes, cardiac reasons for this observation are not clear, hypertrophy, and ischemia) can be traced by but investigation has suggested that one of measurement of serum copper levels, which the effects produced by ischemia is the loss are increasingly viewed as a useful of copper in the heart. 52 Copper prognostic marker. 46 Copper stimulates supplementation can stimulate the factors involved in vessel formation and transcription activity of HIF-1 (Hypoxia- maturation, such as vascular endothelial Induced Factor) and restore angiogenic growth factor (VEGF), which is required capacity, leading to increased capillary for the activation of hypoxia-induced density in the heart. 53 In addition to the factor-1 (HIF-1), an important transcription development of cardiac hypertrophy 48 factor that regulates Expression of VEGF. copper deficiency leads to mitochondrial, The essential role of copper in the structural cardiac alterations and changes in production of VEGF makes it important, for oxidative phosphorylation. 54,55 In situations example, in anti-angiogenesis therapy, such of changes in copper metabolism, such as as the application of copper chelating agents Wilson's disease, cardiac arrhythmias, in cancer therapy. However, suppression of diastolic dysfunctions, cardiomyopathies angiogenesis is involved in the progression and sudden cardiac death are rare of cardiac hypertrophy, so much so that complications, but can be seen mainly in

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How to cite this article: Nunes KZ, Fioresi M. Cardiovascular toxic effects of copper. Salus J Health Sci. [online journal] 2016;2(3):28-36. Available at: http://www.salusjournal.org