Metals and Cardiovascular Disease☆

13.23

Metals and Cardiovascular Diseaseq

A Barchowsky, University of Pittsburgh, Pittsburgh, PA, United States AC Ufelle, Slippery Rock University, Slippery Rock, PA, United States © 2018 Elsevier Ltd. All rights reserved.

13.23.1 13.23.2 13.23.3 13.23.3.1 13.23.3.2 13.23.3.3 13.23.3.4 13.23.5 References

Overview of Metal Exposures Mechanisms of Metal Action Pathogenic Actions of Metals in the Heart Metal-Induced Cardiomyopathies Metal-induced Cardiac Arrhythmias Metal-Induced Ischemic Diseases and Atherosclerosis Angiogenesis Conclusions

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Abbreviations ARE Antioxidant response element CVD Cardiovascular disease hERG Human ether-a-go-go related gene HIF-1a Hypoxia-inducible factor-1a IRE Iron response element IRP Iron regulatory protein LDL Low-density lipoprotein LQTS Acquired long QT syndrome MTF-1 Metal-responsive element-binding transcription factor-1 NADPH Oxidase Nrf2 Nuclear factor E2-related factor 2 PHD Prolyl-4-hydroxylase SRE Stress response element TRPM7 Transient receptor potential melastatin, type 7 (TRPM7)

13.23.1

Overview of Metal Exposures

The majority of the elements in the periodic table are metals or metalloids. However, most of these are not toxic and many are essential to health. As elements, unlike other toxicants, they can be redistributed but not destroyed in the environment. The main routes of exposure to metals include ingestion of food and water, as well as inhalation of particles and fumes. In general, exposures to high, acutely toxic levels of many metals have been reduced by present-day occupational and environmental standards. In contrast, exposures to the rarer metals, such as indium, gallium, or gadolinium, are increasing as they are used in manufacture of electronic components and advanced imagining technologies. Many of the toxicities of these rare metals and their alloys found in novel applications (e.g. gallium arsenide semiconductors or nanoparticles) are yet to be discovered. A major tenant of metal toxicity is that the form and valance of the metal dictates the hazard and as metals are being produced in novel forms, such as the nanoparticles that can enter the circulatory system, there is increased concern with risks of CVD. In addition, chronic low level environmental metal exposures are highly relevant to the health of hundreds of millions of humans worldwide and the cardiovascular toxicities of these exposures may significantly contribute to what is often termed idiopathic disease. The cardiovascular system is a primary target of metal toxicities with endothelial cell dysfunction often occurring before toxicity in many parenchymal cells. This was elegantly demonstrated by several groups for cadmium-induced liver toxicity. Infusions of cadmium into rats caused liver endothelial cells to lose junctional integrity and slough before evidence of hepatocyte injury was

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Change History: May 2017. A Barchowsky and AC Ufelle, added new abstract. Text of the article revised, references updated, section on hypertension as the metals produce hypertension more through renal effects than vascular effects eliminated, references updated. This is an update of Barchowsky, A., Metals and Cardiovascular Disease, Comprehensive Toxicology, Second Edition, edited by Charlene A. McQueen, Elsevier, Oxford, 2010, Volume 6, Pages 447–463.

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apparent (reviewed in Prozialeck et al., 2006). These studies also demonstrated that toxicity depended on increased uptake of the metal by the endothelial cells relative to hepatocytes and genetic differences in the uptake mechanism (Liu et al., 1992; McKim et al., 1992). The relevance of cadmium injury to the endothelium and vasculature comes from a prospective epidemiological study that found urinary cadmium levels are associated with cardiovascular mortality and increased incidence of CVD (Tellez-Plaza et al., 2013). The increasing numbers of prospective longitudinal studies demonstrating the potential for other environmental metals, such as cadmium, arsenic and lead (Cosselman et al., 2015), and findings of the TACT (Trial to Access Chelation Therapy) study that chelating metals reduced cardiac events in stable post-myocardial infarction patients (Lamas et al., 2016) emphasize the importance of metals in promoting CVD. Metals promote cardiovascular morbidity of mortality by augmenting or perturbing well characterized pathways of CVD, such as pre-clinical development of atherosclerosis, triggering of ischemic events, generation of arrhythmias, and altering cardiac function. These actions are both concentration and temporally related, although the concentration-response relationships for metal toxicities are complicated by differential tissue and cellular responses. Determining the dose or concentration of the active form of a metal at the tissue or cellular level remains difficult. This inability further complicates establishing accurate dose-response relationships when determining disease risks. Tissue uptake, which may influence metal effects on that tissue’s vasculature (e.g. renal and testicular vascular toxicities of cadmium), and the biological half-lives of metals vary greatly. Dietary factors may also dictate the bioavailability or action of the metal making demonstration of causal relationships for the metals in disease etiology difficult. Preferential uptake of metals into the different types of cardiovascular cells or their organelles significantly influences the variety of pathophysiologic effects of the different metals. Uptake of the metals, their intracellular actions, and their cellular efflux depend on both the oxidation state of the metal and a number of selective transport and binding proteins. For example, trivalent arsenic (arsenite) is generally several orders of magnitude more toxic than pentavalent arsenic (arsenate) due to rapid uptake of arsenite through aquaporins relative to poor uptake of arsenate that competes with phosphate for cell entry (Yang et al., 2012). However, once inside the cells, both species of arsenic exert actions on signaling or metabolic function with arsenite binding to critical sulfhydryls in proteins or arsenate mimicking phosphate in phosphotransfer reactions (Ralph, 2008). The oxidation states of iron and copper are also critical for their exchange between binding and transport proteins, as well as their cellular actions and catalysis of redox reactions. Cadmium is actively transported into cells and due to binding to intracellular chaperone proteins, such as metallothionein, may have a biological half-life in the kidney of 20–30 years. Arsenic on the other hand, freely follows water through aquaporins or is rapidly pumped out of cells for excretion in the urine (Yang et al., 2012) with a biological half-life of 12–24 h. Metals are rarely free in the circulation or inside of cells. Instead, a number of selective metal transporters and chaperone proteins tightly bind the metals to facilitate tissue distribution and storage. It is the free or labile pool of the metal that participates in toxic actions. Primary examples of the importance of sequestering proteins in preventing cardiovascular toxicity are seen with copper or iron binding proteins and transporters. Copper release from the gastrointestinal enterocytes into the blood and elimination from hepatocytes into bile are regulated by the Cuþ-transporting P-type ATPases, ATP7A and ATP7B respectively. Mutations in these two proteins cause either Menkes or Wilson’s diseases that both present with cardiovascular sequelae. Menkes disease (ATP7A mutation) is an X-linked lethal disorder of intestinal copper hyperaccumulation with severe copper deficiency in peripheral tissues. This causes deficits in copper-dependent enzymes that lead to the clinical hallmarks of the disease including abnormal vascular development (Kim et al., 2008; Qin et al., 2006). While free or labile copper participates in oxidant generation, copper deficiency may make the vasculature more prone to oxidative stress due to a reduction in copper in circulating, extracellular superoxide (SOD3) (Qin et al., 2006; Klevay, 2016). Wilson’s disease (ATP7B mutation) is autosomal recessive disease characterized by striking hepatic and neuronal copper overload with oxidant stress (Kim et al., 2008), as well as left ventricular remodeling and a relatively high frequency of benign supraventricular tachycardias and extra systolic beats (Hlubocka et al., 2002). The majority of copper is bound to ceruloplasmin and expression of this transporter in the liver is tightly linked to circulating copper levels. Likewise, circulating iron is primarily bound to transferrin and uptake of transferrin by its cell surface receptor and intracellular iron transfer for storage in ferritin are tightly regulated by expression of the respective proteins. Labile iron binds to iron regulatory proteins (IRPs/aconitase) that bind and regulate iron response elements (IREs) on the 30 - and 50 - untranslated regions of their respective mRNAs (Pantopoulos et al., 2012). In iron deficiency, IRP bound to DNA increases transferrin receptor mRNA stability and blocks translation of ferritin mRNA. In overload, iron-bound IRP is released from the mRNAs to destabilize the transcripts or enhance translation, respectively. Again, the purpose is to tightly regulate the labile iron pool to provide enough essential metal for enzyme reactions without providing excess iron that catalyzes ROS generation and enhances damage to the vessel walls (Brewer, 2007). Another example of the importance of metal transport proteins is the increased endothelial surface expression of a specific cadmium transport protein. This protein, ZIP8, is highly expressed on testicular endothelial cells and promotes hyperaccumulation of the metal that confers sensitivity to cadmium-induced testicular ischemia following endothelial cell injury and vascular leak (Prozialeck et al., 2008).

13.23.2

Mechanisms of Metal Action

There are multiple mechanisms through which metals exert their effects on cardiovascular cell functions. These can be broken down into direct effects caused by directly competing with endogenous essential metals and binding of the metal to a critical protein or enzyme substrate or indirect effects mediated by increased ROS formation. A number of metals at high concentrations interfere with

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ion channels, such as calcium channel interference by nickel, cobalt, magnesium, manganese, cadmium, and lead or potassium channel interference by thallium. However, this inference may be relevant only to acute toxicity caused by very high occupational or accidental exposures (e.g. arrhythmias in hypermagnesemia resulting from errors in therapeutic ion replacement), since the concentration of the interfering metal needs to be in excess of the endogenous metal (e.g. greater than 2.5 mM extracellular calcium). In contrast, direct ligand binding is the most fundamental chemical process in metal-stimulated cell signaling, toxicity, and cellular defenses against metal toxicity. Depending on their oxidation state, metals readily react with sulfhydryls, carbonyl, or phosphate groups. For example, coordination chemistry of copper ions varies with charge, since Cu1 þ prefers sulfur donor ligands, such as cysteine or methionine. In contrast, Cu2 þ prefers nitrogen donors such as histidine or oxygen donors such as glutamate or aspartate (Kim et al., 2008). When bound as the divalent cation, copper is capable of enzyme inactivation through redox cycling and ROS generation (Gokhale et al., 2007). The strong interaction of many metals with sulfur in cysteine and nitrogen in histidine provides for coordination of the metals in the catalytic centers of enzymes and provides tertiary structure for ligand recognition. This is evident in the cys/cys or cys/his coordination of zinc in its essential role in hundreds of enzymes and structural proteins, including protein kinase C family members that provides lipid cofactor binding and in the zinc finger transcription factors that provide specificity for binding DNA sequences. Displacement of essential metals from coordination complexes is an important axis for toxicity (Kitchin and Wallace, 2008; Hartwig, 2001; Hartwig et al., 2002). In the normal cell, there is rarely any free metal ions, since they can be toxic. The total intracellular concentration of zinc is 200 mM, but the free ion concentration is on the order of pM to low nM. Displacement of metals from storage proteins, such as cadmium or zinc release from the multiple cysteine binding sites in metallothionein or release of iron from ferritin, result in the indirect cellular actions of some metals. A common mechanism for metal-induced secondary effects comes from increasing free concentrations of endogenous metals to produce adverse signaling, such as in the case of mobilizing intracellular free calcium or mitochondrial calcium leak that is secondary to exogenous metal-stimulated ROS generation. The indirect ROS-mediated cell signaling and increased oxidative stress are defined by both the level of ROS generated and mechanism of generation (Fig. 1). Signal-generated low levels of ROS, such H2O2, are second messengers for many receptormediated vasoactive and mitogen responses and high ROS levels from respiratory bursts or mitochondrial injury overwhelm cellular antioxidant defenses, promote mitochondrial calcium leak, and damage or kill cells. Generation of ROS through indirect signaling or direct metal-catalyzed reactions depends on both the metal concentration and the ability of the metal to coordinate electron transfer in redox reactions. Several metals, such as free iron and copper, are catalysts that propagate formation of cell membrane damaging oxygen-centered lipid radicals and peroxides, as well as incomplete reduction of molecular oxygen through Haber-Weiss and Fenton reactions with superoxide and H2O2. Fe2þ þ O2 /ðFeO2 Þ2þ ðOxidantÞ/Lipid, Lipid, þ O2 /LipidOO, Fe2þ þ H2 O2 /Fe3þ þ, OH þ OH The end result is generation of lipid or hydroxyl radicals that react indiscriminately with macromolecules and are capable of damaging proteins and DNA (Galaris and Pantopoulos, 2008; Kim et al., 2008). These damaging reactions are only relevant to promoting macromolecule degradation and cell death, since reactivity of the radicals is diffusion limited and too random to coherently affect cell signaling. In contrast, most cardiovascular toxic metals are not capable of catalyzing oxygen centered radical

Fig. 1 Mechanisms for metal stimulated or catalyzed increases in ROS. (1) Metals, such as Fe, Cu, and Co, redox cycle to catalyze generation of damaging oxygen and lipid radicals and peroxides. (2) Metals, such As, act through cell signaling to activate NADPH oxidase (NOX) catalyzed generation of superoxide (O2_) that is then dismutated to generate H2O2, a second messenger in signal amplification cascades. NOX generated superoxide rapidly reacts with nitric oxide (_NO) to form peroxynitrite (ONOO). Formation of peroxynitrite both forms a potent oxidant and decreases nitric oxide levels required for endothelial cell-dependent vasodilation. This mechanism is similar to mitogenic signals stimulated by ligands, such as angiotensin II or platelet-derived growth factor, for G-protein coupled (GPCR) or growth factor (GF) receptors, respectively. (3) Mitochondrial injury following metal disruption of respiration and mitochondrial membrane potentials represents the largest source of ROS in metal toxicity. In addition, ROS generated in mitochondrial injury cause the release of large amounts of calcium (Ca2 þ) that affects cell signaling and cell death.

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or peroxide generation at concentrations relevant to human exposures and under biological or physiological conditions. Instead, they indirectly act on signaling for increased NADPH oxidase-generated ROS or disrupt mitochondrial enzymes to collapse respiration and initiate apoptotic cascades. Often the mechanisms for metal toxicity to cardiac or vascular cells are confused by biphasic concentration response relationships. Functional or phenotypic changes usually occur at low metal concentrations and apoptosis or necrosis occurs at metal levels that promote overwhelming ROS generation. For example, arsenic has both positive and toxic effects on vascular cells that can be prevented by increasing antioxidant capacity. Low, environmentally relevant levels of arsenic stimulate both endothelial and smooth muscle cell NAD(P)H oxidases (Lynn et al., 2000; Straub et al., 2008; Smith et al., 2001) to rapidly increase superoxide generation. This rapid increase results from upstream signal amplification and brings Rac1 or cdc42 GTPase to the membranebound NADPH complex (Lynn et al., 2000; Straub et al., 2008, 2009; Smith et al., 2001). Inhibiting or eliminating these monomeric GTPases inhibits arsenic-stimulated NAD(P)H oxidase activity in vascular cells (Qian et al., 2005; Smith et al., 2001). The levels of superoxide and hydrogen peroxide generated by NAD(P)H oxidase in response to arsenic or other metals are in keeping with the amount of ROS generated by the enzyme when cells are stimulated by endogenous peptides or lipids, such as angiotensin II, platelet-derived growth factor, or sphingosine-1-phosphate. These endogenous peptides and lipids are known to be smooth muscle cell mitogens, pro-angiogenic, and hypertensive. Excess signaling in response to these ligands is known to be a longitudinal cardiovascular disease risk factor (Lee and Griendling, 2008; Peters and Alewijnse, 2007) and metals, such as arsenic, can stimulate NADPH oxidase and cell signaling through prolonged G-protein coupled receptor activation (Straub et al., 2009; Klei et al., 2013; Garciafigueroa et al., 2013). Higher concentrations of arsenic promote lethal oxidant stress in endothelial cells by targeting mitochondrial enzymes and interfering with phosphotransfer reactions (Luz et al., 2016; Samikkannu et al., 2003). These levels are relevant to the toxicity promoted in therapies designed to destroy tumor blood supplies (Roboz et al., 2000; Echaniz-Laguna et al., 2012; Finsterer and Ohnsorge, 2013). Due to their roles in enzymes and structural proteins, essential metal deficiency can also cause vascular disease. Copper deficiency increases oxidant stress and vascular toxicity by decreasing the activity of copper-containing antioxidant enzymes, such as intracellular Cu/Zn SOD, eSOD3, as well as enzymes essential for homocysteine metabolism (Klevay, 2016; Qin et al., 2006). Oxidative stress from copper deficiency compromises the immune system resulting in increased virulence of cardiac pathology from amyocarditic and myocarditic viruses (Kim et al., 2008; Smith et al., 2008). Hypercholesterolemia and increased oxidized LDL, both major CVD risk factors, are consequences of copper deficiency (Klevay, 2016). Also, copper, as well as iron, combines with homocysteine to promote pro-atherosclerotic LDL oxidation and enhanced oxidative vessel injury in aging (Brewer, 2007; Klevay, 2016). Metals influence gene transcription by directly binding to transcription factors. In addition to iron-responsive IRP/aconitase, there are several important regulators of transcription that are metal responsive and induce genes encoding proteins for adaptation, defense through metal sequestering, and stress toxicity. The metal-responsive-element-binding transcription factor-1 (MTF-1) contains six zinc finger motifs that are critical to its ability to transactivate important protective genes, such as the metallothioneins (Heuchel et al., 1994; Laity and Andrews, 2007; Wu et al., 2013). The protein responds only to zinc and stimulation of MTF-1 transactivation by other metals results from displacing zinc from intracellular pools, such as metallothionein itself, or indirect signaling effects on MTF-1 post-translational modifications. Deficiency of MTF-1 greatly contributes to the general toxicity of metals in many tissues, but also specifically to toxicity in vascular endothelial cells (Prozialeck et al., 2006). Nuclear factor-E2 related factor 2 (Nrf2) is another metal responsive factor that regulates transcription of protective or stress response genes. Metals either directly or indirectly promote oxidation of key thiols in the cytoplasmic anchor protein KEAP1 and its posttranslational phosphorylation. Modified KEAP1 releases Nrf2 allowing Nrf2 nuclear transport and transactivation of antioxidant response elements (ARE) or stress response elements (SRE) in the promoters of genes encoding protective metabolic enzymes, such as hemooxygenase-1 and thioredoxins, and enzymes involved in glutathione synthesis (Dinkova-Kostova et al., 2005; Sakurai et al., 2005; Mimura and Itoh, 2015; Chen et al., 2015). However, excessive Nrf2 activity or Nrf2 activity in pro-atherogenic cell phenotypes can also contribute to CVD (Mimura and Itoh, 2015). Another significant target for metal-induced gene expression is the hypoxia-inducible factor-1a (HIF-1a), a transcriptional regulator of a large range of cardiovascular genes (Bishop and Ratcliffe, 2015; Hanze et al., 2007; Shohet and Garcia, 2007). In normoxia, HIF-1a protein is rapidly degraded following post-translational hydroxylation of conserved proline residues in a region of the peptide referred to as the oxygen-dependent degradation (ODD) domain. This hydroxylation is catalyzed by 2–oxoglutaratedependent prolyl-4-hydroxylases (PHD), which contain iron, and the hydroxylated proline residues in the ODD facilitate proteosome degradation following recognition by the von Hippel-Lindau protein. HIF-1a is a major factor in induced cardiovascular protection, especially in late stages of preconditioning for protection against cardiac and ischemic injury (Loor and Schumacker, 2008; Bishop and Ratcliffe, 2015). However, HIF-1a participates in pathological vessel remodeling as well, such as in tumor angiogenesis (LaGory and Giaccia, 2016) and pulmonary arterial remodeling that leads to pulmonary hypertension (Hanze et al., 2007) and consequently cardiomyopathy. The PHDs are targets of many metals, although there appears to be little commonality amongst the metals (e.g. nickel, cobalt, or arsenic) in their mechanism of affecting PHD destabilization of HIF-1a. Low concentrations of cobalt mimic hypoxia to cause HIF-1a-induced preconditioning and improved cardiac contractility (Endoh et al. 2000). Similar preconditioning by cobalt infusions protects against ischemic injury in a variety of tissues (Matsumoto et al. 2003; Sharp et al. 2001). In contrast, cadmium inhibits myocardial hypoxic preconditioning by preventing HIF-1a stabilization and gene transactivation (Belaidi et al., 2008). It is important to remember that transcription factors are highly interactive in complexes that transactivate or repress gene transcription in both protection and cardiovascular disease etiology (Adhikari et al. 2006). In fact,

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metal induction of metallothioneins may result from interactions between both activated MTF-1 and HIF-1a (Murphy et al., 2008). Further, it is clear that there are addition epigenetic layers of regulation with both histone and DNA modifications that are affected by metals and contribute to the pathogenesis is metal-induce cardiovascular diseases (Cosselman et al., 2015).

13.23.3

Pathogenic Actions of Metals in the Heart

13.23.3.1 Metal-Induced Cardiomyopathies Cardiomyopathies, especially dilated cardiomyopathy, are significant diseases of the heart muscle characterized by progressive cardiac dilation and contractile dysfunction, often with signs of hypertrophy. Most cases of dilated cardiomyopathy are idiopathic and the importance of metal-related cardiomyopathies is underscored by reports of elevated trace metals in cardiac tissues of patients with idiopathic dilated cardiomyopathies (Frustaci et al. 1999). In general, metal-related myopathies are chronic diseases rather acutely toxic stress effects on myocardial cells or blockage of myocyte ion channels. Such acute effects would more likely result in arrhythmias, as discussed below. Trace elements claimed to account for idiopathic disease include cadmium (Prozialeck et al., 2006), mercury (Frustaci et al. 1999), antimony (Frustaci et al. 1999), and arsenic (Kang 2001; Li et al., 2002). However, there have also been a number of reports of cobalt leaching form metal prostheses causing fatal cardiomyopathies (Fox et al., 2016; Mosier et al., 2016; Packer, 2016). Iron overload also produces cardiomyopathies; however, these overloads are often associated with genetic diseases, such as thalassemia (Berdoukas et al., 2015; Gammella et al., 2015). In contrast to the other metals, copper deficiency has been implicated in the pathogenesis of cardiomyopathy which is a frequent cause of death in Fredrick ataxia (Kruger et al., 2016). Metals may enhance the efficacy of other toxicants in causing myopathies, such as reports of patients presenting with often fatal cardiomyopathies after consuming alcoholic beverages contaminated with either cobalt (Packer, 2016; Weber, 1998) or arsenic (Klatsky, 2002). In contrast, deficiencies in essential metals, especially copper, zinc, and selenium, enhance myopathies due to increased oxidative stress or enhanced virulence of myocarditic strains of viruses (Jiang et al., 2007; Smith et al., 2008). The latter may be mediated by increased inflammatory responses and decreased innate immune responses due to lack of copper or selenium containing antioxidant and protective enzymes (Smith et al., 2008). There are multiple mechanisms through which the metals alter myocardial cell function to produce dilated myopathies. Disrupting energy production by direct metal binding to cysteines in critical mitochondrial enzymes is a primary mechanism for cadmium, cobalt, mercury, and arsenic-induced myopathies. Cadmium accumulates in the heart and binds complex III in the mitochondrial respiratory chain to uncouple oxidative phosphorylation and increase mitochondrial release of oxidants (Prozialeck et al., 2008). Higher levels of cadmium interfere with intracellular calcium mobilization, but it is not clear whether this is a primary effect or secondary to the increased oxidant stress (Prozialeck et al., 2008). Chronic low level cadmium exposures may targetsthe vascular endothelial cells in the heart microvessels, instead of myocytes, to cause myopathies (Prozialeck et al., 2006). Cadmium decreases vascularization of the heart by promoting endothelial cell dysfunction and loss of junctional integrity (Prozialeck et al., 2006). It is not clear whether this effect is linked to mitochondrial enzyme inhibition or more direct effects on adhesion molecules and proteins in VE-cadherin-dependent junctions that maintain endothelial cell integrity. Chronic cobalt exposure targets mitochondrial enzymes in complex II and complex III, with modest effects on respiration and a minimal lowering of ATP levels (Packer, 2016; Clyne et al., 2001). These exposures cause pronounced decreases in mitochondrial manganese superoxide dismutase levels in rat hearts, which may contribute to oxidative myocardial injury (Clyne et al., 2001). In addition, cobalt-stabilized HIF-1a increases expression of endothelin-1, which would signal for cardiac hypertrophy and remodeling (Kakinuma et al., 2001).

13.23.3.2 Metal-induced Cardiac Arrhythmias Metals disrupt cardiac electrical conduction through several mechanisms. The simplest mechanism is interference with or blockage of calcium, potassium, or sodium channels. High (mM) concentrations of nickel are commonly used in research to block cardiac calcium channels and magnesium toxicities in hypermagnesiumemia also relate to calcium ion channel blockade. However, these actions occur when circulating concentrations of the interfering metal exceed blood calcium concentrations and thus relate only to acute accidental or adverse clinical exposures. In contrast, acquired long QT syndrome (acLQTS) is a significant dose-limiting side effect of antileukemic arsenic therapies that occurs when circulating arsenic concentrations approach 5 mM (Dennis et al., 2007; Roboz et al., 2014). Prolonged QT intervals have also been associated with chronic environmental exposures to arsenic in drinking water when circulating arsenic levels are often sub-micromolar (Mumford et al., 2007; Wu et al., 2014). LQTS reflects slowed ventricular repolarization at the cellular level and is characterized by a prolongation of the QT interval on the electrocardiogram. As a direct consequence of abnormal repolarization in LQTS, arsenic-sensitive patients may present with syncope, torsades de pointes, arrhythmias, or sudden cardiac death (Dennis et al., 2007). The cardiac hERG (human ether-a-go-go related gene) potassium channel is the a-subunit of the rapid delayed rectifier current IKr in ventricular myocytes. This channel contributes prominently to terminal repolarization and is the target of many chemicals and therapeutics that cause acLQTS (Dennis et al., 2007; Cubeddu, 2016). However, in contrast to most of these agents that bind and block the channel, arsenic is devoid of direct acute effects on cardiac repolarization or inhibition of hERG/IKr (Dennis et al., 2007). Instead, arsenic reduces trafficking of hERG/IKr to myocyte membranes by affecting molecular chaperone proteins, such as Hsp90 (Dennis et al., 2007).

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Trivalent antimony, which is cardiotoxic and similar to trivalent arsenic, also inhibits hERG/IKr trafficking (Dennis et al., 2007). Pentavalent antimony is a mainstay in treating humans for leshmaniasis and schistosomiasis. However, its use is limited by severe cardiac side effects after conversion to the trivalent form. Trivalent antimony is acutely cardiotoxic and causes pronounced EEG alteration with QT prolongation and ST wave flattening (Alvarez et al., 2005; Kuryshev et al., 2006). In addition to effects on the ion channels, antimony impairs ventricular muscle contractility. These effects are related to mitochondria stress that can be prevented by feeding L-carnitine to preserve b-oxidation of fatty acids (Alvarez et al., 2005). Thus, antimony like arsenic can produce dysrhythmias both by affecting ion channel expression and by causing myocyte injury (Kuryshev et al., 2006). Zinc represents a significant soluble component of some particulate matter that has been shown to contribute to cardiac injury both in vivo and in isolated cardiac myocytes (Campen et al., 2001; Graff et al., 2004; Kodavanti et al., 2008). Acute and prolonged exposure of cultured rat ventricular myocytes to zinc reduced spontaneous beat rates and differentially induced expression of a number of potassium channel proteins (Graff et al., 2004). In vivo, intratracheal or nose only exposure of WYK rats to environmentally relevant zinc-containing PM for 8–16 weeks decreased the number of myocardial granulated mast cells, and produced multifocal myocardial degeneration, chronic-active inflammation, and fibrosis, relative to rats exposed to clean air or non-zinc containing PM (Kodavanti et al., 2003, 2008). At the cellular level, these zinc PM exposures caused ventricular cell mitochondrial enzyme inhibition (Kodavanti et al., 2008). In addition to confirming that genes involved in ion channel function were induced, this study found zinc caused modest changes in gene transcripts encoding signaling, oxidative stress, mitochondrial fatty acid metabolism, and cell cycle regulating proteins.

13.23.3.3 Metal-Induced Ischemic Diseases and Atherosclerosis Arteriosclerosis, and especially atherosclerosis, or occlusive disease is the most common pathologic process underlying cardiovascular diseases and can be systemic or confined to individual organs. Environmental exposures to metals, such as cadmium and arsenic (Messner et al., 2009; Solenkova et al., 2014), as well as seemingly normal accumulation of iron or copper may play a role in atherogenesis. However, many large epidemiological and clinical studies provide conflicting conclusions of direct causal relationships and potential mechanisms. The roles of iron and copper in the etiology of atherosclerosis related to aging have been extensively studied (Brewer, 2007; Klevay, 2016). There is stronger evidence that levels of iron and copper that are normal and adequate in reproductive years become clear risks for age-related atherosclerosis (Brewer, 2007). Many of the studies that failed to find an association of iron or ferritin levels with disease failed to accurately measure the labile pool of iron that would participate in oxidative injury to the cardiovascular tissues (Brewer, 2007; Vinchi et al., 2014). In addition to citing support from definitive, well controlled animal studies, a recent review of the literature indicates that mechanistic studies provide clear evidence that there is high level iron deposition in human atherosclerotic lesions, that H- and L ferritin mRNAs are higher in human and rabbit atherosclerotic vessels than in normal ones, that iron with ceroid colocalize in human atherosclerotic tissue, and that iron chelators inhibit low-density lipoprotein (LDL) oxidation (Vinchi et al., 2014; Brewer, 2007). In addition, as discussed for copper, labile iron and homocysteine co-operate to enhance oxidant generation and atherogenic lipid oxidation that contributes to disease etiology (Pfanzagl et al., 2003). Many mechanistic studies, however, fail to make causal links between critical, rate-limiting iron effects in atherosclerotic pathogenesis that are distinguished from effects that result from the general atherogenic progression and more careful studies are called for (Vinchi et al., 2014). Environmental exposures to arsenic in drinking water (Engel et al., 1994; Moon et al., 2012, 2013; Cosselman et al., 2015; Chen et al., 2011; James et al., 2015) or occupational exposures through inhalation (Hertz-Picciotto et al., 2000; Cosselman et al., 2015) have been linked to increased cardiac ischemic diseases and infarctions. Early reports in Taiwan associated arsenic exposures with thickened coronary and carotid arteries, even years after exposures cease (Tseng et al., 2003; Wang et al., 2007). More recent evidence from carefully controlled studies of widespread exposures in Bangladesh and the United States indicate that chronic low-moderated arsenic exposures promote CVD, especially ischemic disease by increasing long term vascular inflammation, promoting endothelial cell dysfunction, stimulating smooth muscle cell growth, and elevating expression of circulating adhesion molecules that regulate pathogenic leukocyte/endothelial cell interactions (Wu et al., 2014; Cosselman et al., 2015). Animal studies using human relevant drinking water arsenic exposures provide recapitulate observations of enhanced endothelial cell leukocyte adhesion molecules and mechanistic insight into arsenic promotion of early stage atherogenesis (Lemaire et al., 2015). These studies further demonstrate that arsenic impairs the actions of lipid regulating transcription factors to activates macrophages and induces vessel and plaque remodeling metalloproteinase to favor solid plaque formation (Lemaire et al., 2011, 2014). Other studies have indicated that direct damage to the endothelial cell monolayer, altered nitric oxide metabolism, and possibly loss of barrier function may contribute to arsenic-induced atherogenesis in adult rodent models (Bunderson et al., 2004; Pereira et al., 2007). There is strong evidence that, as with endogenous risk factors for atherosclerosis, arsenic signaling in both endothelial and smooth muscle cells stimulates NADPH oxidase generation of atherogenic ROS. In vivo studies in a genetic mouse model demonstrated that endothelial NADPH oxidase is essential for liver vessel remodeling, as well as loss of the endothelial scavenging of damaged proteins and lipids that pose atherogenic risk (Straub et al., 2008). As mentioned above, these studies also found that arsenic stimulated NADPH oxidase by activating the endothelial sphingosine-1-phosphate type 1 receptors (Straub et al., 2009). Blackfoot disease is a unique peripheral vascular disease found in certain populations exposed to high levels of arsenic in their drinking water (Moon et al., 2012; Tseng et al., 2005). First described in endemic regions of southwest Taiwan, this disease is a form of arteriosclerosis obliterans that promotes systemic ischemic disease, dry gangrene and spontaneous amputation of the affected

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extremity. Blackfoot disease has also been described in mining areas of Central and South America. An epidemic of a similar peripheral vascular disease was seen in German vintners; although this form may have resulted from combined effects of arsenic and alcohol exposure (Engel et al., 1994; Klatsky, 2002). Recent evidence suggests that those who are at the highest risk for arsenic-related Blackfoot or other peripheral ischemic disease are those who not only consume high levels of arsenic, but also have reduced arsenic methylation capacity and produce less of the dimethylated excreted form of arsenic (Tseng et al., 2005). In support of this mechanism, males are more prone to arsenic-related peripheral vascular disease and have reduced methylating capacity compared to females (Tseng et al., 2005) Cadmium exposure has been positively linked to atherosclerosis and peripheral vascular disease (Cosselman et al., 2015; Solenkova et al., 2014; Larsson and Wolk, 2016). Chronic exposures of rodents to low levels of cadmium enhance atherogenesis and hypertension and these effects can be opposed by increasing dietary intake of selenium and zinc. This protection may result from increased expression of metallothioneins, cadmium sequestering proteins. The mechanism for cadmium-promoted atherogenesis appears to be endothelial cell dysfunction and injury (Prozialeck et al., 2006). Cadmium induces release of a several proinflammatory mediators from endothelial cells and it stimulates the release of antithrombolytic agents to facilitate adhesion of leukocytes and platelets to the vessel wall (Jeong et al., 2004; Prozialeck et al., 2006). These factors combined with cadmium’s effect of decreasing endothelial junctional integrity and barrier function would contribute to atheroma formation. In addition, cadmium promotes smooth muscle cell proliferation and enhances the extracellular matrix production to increase vessel wall stiffness. Finally, cadmium produces a unique and intense ischemic injury in rodent testes that is promoted by cadmium concentration due to highly expression levels of the ZIP8 metal transporter on the testicular endothelial cells (Prozialeck et al., 2008). Lead exposure, although declining in many parts of the world, is associated with increased risk of ischemic heart disease, stroke, and peripheral vascular disease (Navas-Acien et al., 2004, 2007; Weisskopf et al., 2009; Jain et al., 2007). Lead promotes vascular dysfunction by mimicking calcium and promoting oxidative stress at high levels. It promotes loss of endothelial nitric oxide generation and nitric oxide suppression of smooth muscle proliferation (Vaziri, 2008). Exposure in animal models produce aortic medial thickening and wall stiffening, as well as increased atherosclerotic plaque formation (Vaziri, 2008). Human studies also find increased atherosclerosis and plaque formation associated with elevated lead exposures and these plaques may be related to lead impairing lipid metabolism and increasing vascular oxidative stress by inhibiting serum paraoxanase-1 (Li et al., 2006). While the mechanism for this inhibition is not clear, it has been proposed that the lead exposures cause decreased copper levels that are essential for paraoxonase-1 activities and homocysteine metabolism mentioned above (Klevay, 2007, 2016).

13.23.3.4 Angiogenesis Angiogenesis, the growth of new vessels from pre-existing blood vessels, represents an important axis for metals to promote aberrant remodeling of the vasculature and tumorigenesis. Closely related, neovascularization in development is also affected by different metal exposures and this can contribute to their teratogenic effects. Magnesium and copper are essential for adequate angiogenic responses (Baldoli and Maier, 2012; Urso and Maffia, 2015; Trapani et al., 2013). The actions of both essential metals in angiogenesis are complex and rely on specific transporters and chaperone proteins that have been targeted to inhibit tumor angiogenesis (Trapani et al., 2013; Urso and Maffia, 2015). Eliminating the transient receptor potential melastatin, type 7 (TRPM7) endothelial cell magnesium channel mimics the effects of magnesium deficiency on endothelial cell function and angiogenesis (Trapani et al., 2013). The mechanisms through which copper contributes to angiogenesis include: induction and adequate expression of a number of pro-angiogenic cytokines (Pan et al., 2002); supporting the activity of CuZn SOD1 (Donate et al., 2008; Klevay, 2016); and possibly promoting circulating levels of endothelial cell progenitor cells (Donate et al., 2008). Chelating copper with tetrathiomolybdate has proven to be an effective means of reducing tumor size and burden in many animal models and in phase 1 and 2 human clinical trials. Producing a copper deficient state with chelation both reduces drive for angiogenesis and promotes oxidative injury and apoptosis in the angiogenic endothelium and tumor cells (Donate et al., 2008). However, while this therapy may aid in treating tumors, the copper deficiency increases the risk of cardiovascular disease, as discussed above (Klevay, 2016). Arsenic causes concentration-dependent biphasic effects on angiogenesis. At low to moderate environmental and therapeutic levels, arsenic increases angiogenesis in a number of animal developmental and tumorigenesis models (Kamat et al., 2005; Liu et al., 2006; Soucy et al., 2003, 2005). Higher therapeutic arsenic levels are used to kill angiogenic endothelial cells in tumors (Liu et al., 2006; Roboz et al., 2000; Ralph, 2008) and prolonged exposure of mice to high (> 250 ug/L) arsenic levels caused a loss of cardiac microvessels (Soucy et al., 2005). As indicated above, the therapeutic use of arsenic is limited by the narrow therapeutic window between levels required to kill endothelial cells and those that increase cardiac arrhythmias (Roboz et al., 2014). Arsenic induces angiogenic genes in both endothelial and smooth muscle cells, as well as increased recruitment of inflammatory CD45 positive cells to support full development of patent angiogenic vessels. As discussed above in mechanisms, arsenic stimulates angiogenesis by activating the sphingosine-1-phosphate type 1 receptor and its signaling cascades through Rac1-GTPase, NADPH oxidase, and oxidant responsive transcription factors. This leads to increased expression of pro-angiogenic genes, enhanced endothelial proliferation, and new vessel formation (Straub et al., 2009). Toxic levels of arsenic target cysteinecontaining mitochondrial enzymes and interfere with phosphotransfer to decrease ATP levels and collapse the mitochondrial electron gradient. The net result is endothelial apoptosis (Liu et al., 2006; Roboz et al., 2000). It is important to note that inorganic arsenic ingested in drinking water or injected therapeutically is metabolized to methylated species that are even more active on endothelial cells than the parent compound (Hirano et al., 2004). There are also sex differences in methylation capacity that may account for differences for cardiovascular disease incidence or severity between males and females exposed to arsenic (James et al., 2015).

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Human cardiovascular toxicity and disease associated with metal exposures.

Cardiomyopathy Cardiac arrhythmias Ischemic disease Atherosclerosis Hypertension angiogenesis

Antimony

Arsenic

Cadmium

Cobalt

Copper

Iron

þþþa þþa

þþa,b þþþa þþþ þ þ þþ

þ

þþb,c

þþb,d

þþ

þ þ/-e

þþ þ þþþ

þþ þþ þ

Lead

þ/-d

Mercury

Nickel

Vanadium

Zinc

þd þ

þd þþ

þ

þ

þ/-f

þe

The number of þ symbols indicates strength of association with disease or human toxicity. Mixed þ/- indicates a modest association. No symbols imply there are no substantial reports of a relationship. a Dose limiting toxicity in therapies. b Enhanced ethanol-related myopathy. c Protective at low levels. d Enhanced virus related myopathies. e Only secondary to renal injury in high level, acute exposures. f Environmental mercury has a slight effect in children that dissipates by teen years; however accidental high level exposures result in severely elevated blood pressure.

Cadmium inhibits angiogenesis by disrupting intercellular contacts and preventing endothelial cell migration (Prozialeck et al., 2006, 2008). Endothelial cells are relatively resistant to the cytotoxic effects of cadmium. However, non-cytotoxic levels of cadmium inhibit migration and tube formation by disrupting angiogenesis by redistributing VE-cadherin from the endothelial cell surface (Prozialeck et al., 2006, 2008). Inhibitory effects on cell adhesion molecules may also limit endothelial cell interactions with circulating cells that provide for stabile vessel formation. In addition, cadmium inhibition of angiogenesis may be associated with a decreased production of nitric oxide (Prozialeck et al., 2008) and possibly by inhibiting HIF-1a driven gene expression (Belaidi et al., 2008).

13.23.5

Conclusions

As indicated throughout this chapter, environmental, occupational, and accidental metal exposures produce a range of cardiovascular disease promoting effects. These effects may be through direct actions of the metal or secondary to tissue injury caused by selective metal accumulation and oxidative stress. It is clear that certain metals are acutely toxic to both the heart and blood vessels following high levels of exposure. There appears to be a hierarchy of cell sensitivities to acute metal injury with endothelial cells that receive the highest dose of metal being injured before underlying tissues. However, the primary and secondary effects of lower levels of metals that contribute to the etiology of chronic cardiovascular diseases are complex and mechanisms for these effects often remain unresolved. In general, the subtle nature of environmental metal exposures on cardiovascular function and injuries has complicated linkage of exposure to disease etiology or modification. Moreover, several epidemiological studies revealed that certain populations or subgroups of individuals are more susceptible to the cardiovascular effects of metals and that nutrition modifier many of these effects. Without appropriate stratification of epidemiological data to account for these individuals or factors, the true impacts of metal exposures on cardiovascular disease are often lost. Table 1 summarizes the information presented in this chapter regarding the strength of evidence for a role of individual metals in different cardiovascular diseases in humans. It is evident from the large numbers of epidemiological studies, clinical case reports, animal exposure studies, and cells based studies that metal exposures are significant public health concerns that cause unique cardiovascular toxicities and enhance disease risks. The study of the molecular pathogenesis of the different metals is complicated by the bioavailability of the different species of the metals in the environment, interconversion of these species in the circulation or in the cells, uptake of the different species into cells, and differential interactions of the species with cellular macromolecules. These interactions include both activating cell signaling cascades at lower levels of exposure and macromolecule damage or degradation at higher levels. Separating direct effects of the metals on these macromolecules from secondary effects on cell signaling and ROS production complicates the ability to define the initial sites and rate-limiting steps of their cellular actions and toxicities. Despite these limitations, much is known of molecular actions of metals on the individual cells in the cardiovascular system and on the functioning of these cells. It is evident from Table 1 and from the information in this chapter that metal actions in the cardiovascular system cannot be simplified to single mechanisms or modes of action, such as random interactions with thiols or oxidative stress. Instead the individual metals and metal species have unique properties that provide for selectivity in reacting with cellular targets and in mechanisms that initiate or suppress cell functions. More support for toxic mechanisms and disease etiologies is being produced as focus has shifted to understanding etiologies of cardiovascular diseases clearly linked to metal exposures. However, there is still need to direct research towards determining genetic and epigenetic disposition in individuals that are more susceptible to metal-induced cardiovascular disease than others as well as biomarker discovery especially in children to avoid irreversible injuries. Findings from this research and improved understanding of the molecular pathogenesis of metals in the heart and blood vessels will help refine policies that limit metal exposures or prevent injury from these exposures to reduce clinical disease and protect public cardiovascular health. Conversely, better understanding of the role of essential metals in vascular health and the toxic mechanisms of exogenous metals is providing novel targets for vascular toxic therapeutics designed to prevent vascular expansion or angiogenesis.

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