Sage Journals: Discover world-class research

Abstract

Vascular endothelium plays a vital role in the organization and function of the blood vessel and maintains homeostasis of the circulatory system and normal arterial function. Functional disruption of the endothelium is recognized as the beginning event that triggers the development of consequent cardiovascular disease (CVD) including atherosclerosis and coronary heart disease. There is a growing data associating mercury exposure with endothelial dysfunction and higher risk of CVD. This review explores and evaluates the impact of mercury exposure on CVD and endothelial function, highlighting the interplay of nitric oxide and oxidative stress.

Keywords

mercury cardiovascular disease endothelium NO oxidative stress

Cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension, or chronic heart failure alter the regulatory function of endothelium in coronary, peripheral conduit, and resistance vessels. In addition to these risk factors, attention has recently been given to toxic effects of mercury in the cardiovascular system.^1
–3 A growing mass of data now strongly indicates an association of cardiovascular disease (CVD) with mercury exposure.

Mercury, a heavy metal belonging to the transition element series of the periodic table, is widespread and persistent as a pollutant in the environment. Mercury occurs naturally in the environment, anthropogenic activities cause the release of this element into the environment, leading to the pollution of air, water, and soil.^4,5 This element has been in commercial (compact fluorescent lightbulbs, batteries, etc) and medical use (laxative, dental amalgam, etc) for centuries, and human beings are exposed to it.⁴

Mercury exists in 3 forms: metallic mercury (also known as elemental mercury), inorganic mercury, and organic mercury, and its different forms and duration of exposure have different health effects. Exposure to mercury is the second most common cause of heavy metal poisoning. Blood vessels are the primary site of exposure to the toxic effects of mercury, because when mercury enters the body, it reaches the various organs through the circulatory system. Toxicity from mercury is associated with in vivo oxidative stress. Mercury exposure induces the generation of reactive oxygen species (ROS), with subsequent oxidative damage in several organs and systems as well as alters the antioxidant defense system in the cells.^6

–10 Oxidative stress that results in endothelial dysfunction and loss of endothelium-dependent vasorelaxation is one of the most commonly observed cardiovascular effects of mercury exposure.^11

–14

The aim of this review is to explore the relationship between mercury exposure, CVD, and endothelial cell (EC) function/dysfunction, focusing predominantly on interaction/balance between bioavailability of nitric oxide (NO) and oxidative stress.

Mercury and Its Association With Cardiovascular Disorders

Population Studies

An association between the environmental and occupational exposure to mercury and the risk of CVDs was established after follow-up studies of severe cases of poisoning, and studies also showed cardiovascular abnormalities in Iraq and in Minamata, Japan.^15,16 Since then several studies have associated cardiovascular disorders with mercury exposure.^{17

–31} Numerous population studies have reported tachycardia, high blood pressure (BP), decreased heart rate variability (HRV), increase in the risk of stroke, and increased risk of total cardiovascular mortality.^{17,19

–25} In a native population of Quebec (Canada), organic mercury exposure has been associated with increased resting HR but with no significant association with BP.²⁶ In a study conducted on 274 schoolchildren, an increased level of mercury in urine has been associated with elevated cholesterol level, which is a known risk factor for myocardial infarction, coronary disease, and CVD.²⁷ It has always been considered that consumption of fish is beneficial for the health of heart because they are rich in the potent antioxidant and long chain n-3 polyunsaturated fatty acids. However, a number of studies indicate that the consumption of fish contaminated with mercury causes high mercury levels in blood, hair, urine, and toenails, which diminish the cardioprotective effect of n-3 polyunsaturated fatty acids.^28
–30

In a study of 236 healthy people, mercury content in hair due to smoking (cigarettes contain a slight amount of mercury), which in itself is a major risk factor for the development and progression of CVD, was found to be positively associated with increased BP and abnormal lipid metabolism.³¹ Mercury is also associated with decreased HRV among French Polynesian teenagers, with no significant association with resting HR, BP, or Pulse Pressure (PP) among teenagers or adults.³² In 2014, a total of 2114 healthy adults who were not exposed to mercury occupationally were sampled, and it was observed that mercury was associated with metabolic syndrome and parasympathetic dysfunction, indicating that mercury exposure may play a role as a possible risk factor for CVDs.³³

However, data from the Kuopio Ischaemic Heart Disease Risk Factor Study of 848 men and 909 women suggest that hair mercury is not associated with high BP.³⁴ A recent study has demonstrated that there is no association between childhood BP and prenatal mercury exposure.³⁵ The Seychelles Child Development Study has negated the hypothesis that prenatal or recent postnatal methyl mercury exposure from fish consumption is associated with impaired autonomic HR control.³⁶ In another population study, toenail and hair mercury levels in Faeroese whaling men were significantly associated with increased carotid intima–media thickness (IMT) and hypertension,¹⁸ suggesting a greater role of vascular system in the mercury exposure–associated CVDs.

Animal Studies

In animal models of mercury exposure, various cardiovascular effects have been observed. The route, dose, and period of mercury exposure determine the kind of cardiovascular effect caused. A decrease in HR accompanied with an increase in systolic BP has been observed in male rats chronically treated with methyl mercury chloride.³⁷ Chronic exposure of rats to mercuric chloride also causes an increase in BP and decrease in cardiac contractility with no change in HR.³⁸ In a different longer chronic study, positive inotropic response, with increase in BP and cardiac contractility and decrease in baroreceptor reflex sensitivity, was observed. The investigators suggested that the mechanism for the cardiac effects in the chronic study involved the release of norepinephrine from presynaptic nerve terminals.³⁹ Rossoni and coworkers observed that after acute mercuric chloride administration, there was a decrease in arterial BP in anesthetized rats.⁴⁰ da Cunha and coworkers have also observed that in situ administration of mercuric chloride (2 µmol/L) produced a significant increase in the perfusion pressure mediated by the formation of superoxide anions in isolated perfused rat tail vascular bed.⁴¹

Chronic exposure to inorganic mercury also causes a significant increase in left ventricular end diastolic pressure, blood and cardiac tissue mercury content, and myocardial lipid peroxides and attenuates baroreflex sensitivity.⁴² In a similar experimental study, the mice treated for 21 days with a drinking solution of methyl mercury (40 mg/L) showed increased total and non-HDL plasma cholesterol levels, supporting the concept of mercury-induced cardiovascular toxicity.⁴³

Both population and animal studies signify that mercury exposure leads to CVDs, like hypertension, CHD, myocardial infarction, reduction in HRV, increase in sudden cardiac death, increase in carotid IMT and carotid obstruction, generalized atherosclerosis, renal dysfunction, renal failure and proteinuria, and an overall increase in the total cardiovascular mortality.^{1,2,4,28,44

–53}

The beginning event that triggers the development of consequent CVD is the functional disruption of the endothelium or endothelial dysfunction, and there is a growing data associating mercury exposure with endothelial dysfunction and higher risk of CVD.

Physiological Role of Endothelium

The vascular endothelium is a single layer of cells lining the inner wall of the vasculature and functions as a regulator of vascular tone by releasing various vasoactive substances: vasodilators (NO, prostacyclin [PGl₂], endothelium-derived hyperpolarizing factor [EDHF], bradykinin, adrenomedullin, C-natriuretic peptide) and vasoconstrictors (endothelin 1 [ET-1], angiotensin II, thromboxane A2 [TXA2], prostaglandins, hydrogen peroxide [H₂O₂], and free radicals).⁵⁴ The l-arginine–NO pathway is thought to be the most important enzymatic vasodilator source.

The ECs constitutively express a NO synthase (NOS) that generates NO using l-arginine as a substrate. Synthesis of NO is enhanced after Ca²⁺/calmodulin binding. Endothelial NOS (eNOS) is an nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxygenase that requires tetrahydrobiopterin, Flavine adenine dinucleotide (FAD), and Flavine mononucleotide (FMN) as cofactors.^55,56 In ECs, the enzyme is localized preferentially in caveolae following posttranslational acylation.^57,58 In this configuration, NOS is negatively regulated by caveolin. However, stimulation of ECs by agonists, such as bradykinin and acetylcholine, dissociates the caveolin/NOS complex and activates NO synthesis by Ca²⁺/calmodulin binding.^57,58 In addition, shear stress–induced activation of NOS involves a Ca²⁺ independent, protein tyrosine kinase–dependent mechanism.⁵⁹ The relaxation of vascular smooth muscle (VSM) by NO involves the stimulation of soluble guanylate cyclase and consequently the increased formation of cyclic guanosine monophosphate (cGMP).⁶⁰ The latter activates cGMP-dependent protein kinase, which leads to an increased extrusion of Ca²⁺ from the cytosol in VSM and inhibits the contractile machinery.⁶¹ The cGMP-dependent protein kinase phosphorylates K⁺ _ATP channels to induce hyperpolarization and thereby inhibits vasoconstriction.⁶¹ In certain arteries, NO activates K⁺ _ATP channels independently of cGMP⁶² (Figure 1).

Figure 1.

Endothelium-derived vasoactive factors. In response to shear stress and chemical stimuli, such as acetylcholine (ACh), the constitutively expressed endothelial nitric oxide synthase (eNOS) cleaves the substrate l-arginine to form nitric oxide (NO). Cyclooxygenase (COX) pathway-derived prostacyclin (PGl₂) and endothelium-derived hyperpolarizing factor (EDHF) are also released. Endothelin 1 (ET-1) is a potent endogenous vasoconstrictor, which is synthesized from the prohormone big ET by ET-converting enzymes (ECEs) and released in response to hypoxia and angiotensin II among other stimuli. There are 2 separate receptor subtypes, ET_A and ET_B.

In addition to its function as a vasodilator, the NO released from ECs is also a potential inhibitor of platelet aggregation and causes VSM proliferation and nuclear transcription of leukocyte-adhesion molecules including vascular cell adhesion molecule and intercellular adhesion molecule.⁶³ Conversely, the endothelium is able to secrete the potent vasoconstrictor ET-1, which through its proinflammatory and mitogenic effects augments the pathogenesis of CVD.⁶⁴ Other endothelial-derived vasoconstrictors include prostaglandin H2, TXA2, and ROS.

Phospholipids of cellular membranes play an important role as the structural and functional entities in the ECs. Phospholipases are enzymes that specifically hydrolyze the membrane phospholipids and generate bioactive lipid second messengers, which play a vital role in cell signaling.⁶⁵ Phospholipase D (PLD) is one such signaling enzyme, ubiquitously present in all mammalian cells that preferentially hydrolyzes phosphatidylcholine, generating phosphatidic acid and choline.⁶⁵ The PA is further metabolized to either 1,2-diacylglycerol (DAG) or lysophosphatidic acid.^66,67 The formation of DAG activates protein kinase C, which can also contribute to VSM contraction via protein phosphorylation.

Endothelial Dysfunction

Endothelial dysfunction is characterized by a shift in the actions of the endothelium toward reduced vasodilation, a proinflammatory state, and prothrombic properties.⁶⁸ It is associated with most forms of CVD, such as hypertension, coronary artery disease, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure.

Although several processes may lead to endothelial damage, the generation of oxygen-derived free radicals and subsequent lipid peroxidation may be key components in it. Additionally, a fast interaction between NO and superoxide anions results in the formation of peroxynitrite,⁶⁹ which is a less potent vasodilator and possesses the ability to initiate lipid peroxidation.⁷⁰ The accelerated degradation of NO and increased formation of peroxynitrite reduce the availability of endothelium-derived NO. Hence, the endothelium-dependent vasodilatation is maintained at a reduced level. By doing so, there may also be some contribution from the K⁺ _ATP channel pathway.⁷¹

Mercury Exposure, Oxidative Stress, and Vascular Endothelium

Mercury and its derivatives are known to constrict VSM cells. However, only limited information is available on the role of ECs in mercury-induced vasoreactivity. Chronic exposure to mercury is reported to increase vascular resistance and induce hypertension.^17,72 Despite many proposed mechanisms for this relationship, the definitive pathogenesis remains unclear, possibly because individuals exposed to mercury usually display multiple systemic disorders. The proposed mechanisms are typically described by animal model studies on VSMs. Contrary to previous reports that mercury and its derivatives constrict VSM cells, Golpon and coworkers for the first time demonstrated that in the isolated aortic tissue, mercury had a dual effect in the vasculature.¹² At low concentrations, mercury caused an endothelium-dependent vasorelaxation. At higher concentrations, mercury altered the structure and function of vascular endothelium and vasoconstriction was observed. Similar observations were reported by our group ascertaining that mercury exposure produces a biphasic response—vasorelaxation at lower concentrations and vasoconstriction at higher concentrations.⁷³

The ECs secrete oxygen-derived free radicals and H₂O₂ in response to stress.⁷⁴ Superoxide anion inactivates NO,⁶⁹ resulting in vasoconstriction of arteries.⁷⁵ Reactive oxygen species may also facilitate the mobilization of cytosolic Ca²⁺ in VSM cells⁷⁶ or promote Ca²⁺ sensitization of the contractile elements.⁷⁷ The vascular endothelium is very sensitive to metal toxicity–induced oxidative stress.^78
–80 Increase in ROS at high concentrations of mercury chloride results in the cytotoxicity of the EC monolayers, leading to severe EC dysfunction.⁸¹ Correspondingly, Park and Park⁸² have also reported that mercury chloride increases ROS and apoptosis in bronchial epithelial cells.

In bovine pulmonary artery ECs, it has been reported that mercury ions induce oxidative stress through depletion of GSH and inactivation of thiol enzymes.⁸¹ Oxidative stress in vascular ECs on mercury exposure induces the activation of PLD due to the generation of ROS, which results in the generation of DAG, a second messenger for vasoconstriction.⁸³ l-Type calcium channel blockers attenuate mercury-induced PLD activity and demonstrate the importance of calcium and calmodulin in the regulation of mercury-induced PLD activation and the antioxidant potential of l-type calcium channel blockers. Despite the number of studies showing that mercury may induce oxidative stress with subsequent oxidative damage in several organs or systems, the effect of in vivo acute and chronic exposure to mercury on the endothelial modulation of vascular responses is still not well defined.

It has been previously documented that vascular ROS production, plasma malondialdehyde levels, and total antioxidant status increase after both acute and chronic mercury exposure in rats.^{11,14,42,73,85
,87} Low-dose mercury exposure alters the coronary vascular reactivity because of endothelial dysfunction. This at least in part is because of increased ROS production, which is due to the increase in both nicotinamide sdenine dinucleotide phosphate oxidase (NOX): NOX-1 and NOX-4 subunits, suggesting the involvement of NADPH oxidase. A decrease in antioxidant defenses would also contribute to the increased superoxide production observed after mercury treatment.⁸⁶ Contrarily, several authors have reported augmented antioxidant defenses after acute and chronic mercury exposure.^3,14,79 It is therefore possible that antioxidant mechanisms might become activated in mercury-exposed rats to protect cells against the increased oxidative stress. The evidence available suggests that antioxidants may play an important role in abating some health hazards of heavy metals.

Mercury Exposure, Oxidative Stress, and NO Signaling

Furchgott and Zawadzki (1980) discovered that the endothelium releases a substance that relaxes the underlying VSM, which was later shown to be NO or a related compound.^{55,63,87–89}

Studies on isolated aortic rings as previously mentioned indicate that mercury produces a dual/bipasic response. Mercury at higher concentrations alters the structure and function of vascular endothelium and produces vasoconstriction, which is ameliorated by antioxidants super oxide dismutase (SOD), catalase, and l-type Ca channels.^12,73 Vasorelaxation produced at low concentrations of mercury is blocked by the NOS inhibitor Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) and K⁺ _ATP channel blocker, glybenclamide, suggesting that mercury acts through the activation of NOS and K⁺ _ATP channel. It may be that mercury stimulates NOS, which in the presence of l-arginine forms NO. The NO causes synthesis of cGMP, which increases the extrusion of Ca²⁺ from the cytosol in VSM, causing vasorelaxation.⁶⁰ Both cGMP and NO phosphorylate K⁺ _ATP channels to induce hyperpolarization, which results in vasorelaxation.⁶¹ Free radical scavengers along with l-NAME block the mercury-induced vasorelaxant or vasoconstrictor response. The NO-mediated vasorelaxant response is blocked by l-NAME blocks, and the ROS mediated vasoconstrictor response is blocked by SOD and catalase. Mercury causes the vascular endothelium to release both NO and ROS, and it is their ratio that results in the response. If NO produced is more than ROS, a vasorelaxant response is produced. If this ratio is inclined in favor of ROS, vasoconstriction is produced.⁷³

In another in vitro mercury-exposure study, mercury modulated the vascular reactivity. An increase in vascular response to phenylephrine was observed as a result of reduced NO bioavailability due to increased release of ROS.⁸⁵

The interplay between NO and oxidative stress was further validated by an acute exposure study of methyl mercury chloride (5 mg/kg, by mouth) in rats. Oxidative stress was produced along with an increase in serum NO levels. A significant increase in the acetylcholine vasodilator response was observed. This effect was mediated by increased production of NO because of the stimulation of eNOS. It is interesting to note that this increase occurred even when there was oxidative stress, suggesting a state of inclination toward NO⁹⁰ (Figure 2).

Figure 2.

Effect of low/high mercury exposure on endothelium-derived vasoactive factors. In response to low mercury exposure (↑), an increase in the nitric oxide synthase (eNOS) activity/expression causes an increase in nitric oxide (NO) with no effect on prostacyclin (PGl₂) and endothelium-derived hyperpolarizing factor (EDHF). Low mercury exposure also causes oxidative stress, and a fast interaction between NO and superoxide anions results in the formation of peroxynitrite, which causes vasoconstriction. In response to high mercury exposure (↑), decrease in the eNOS activity/expression causes decrease in NO with persistence or upregulation of EDHF. High mercury exposure also causes oxidative stress and a fast interaction between NO and superoxide anions, resulting in the formation of peroxynitrite, which causes increase in vasoconstriction.

Contrary to above, an opposite interaction between NO and oxidative stress was observed in a chronic study of healthy Wistar rats exposed to inorganic mercuric chloride in drinking water for 30 days. Oxidative stress accompanied with increased NO levels and endothelial dysfunction was observed. Although there was an increase in the serum NO level, endothelial dysfunction was detected. As there was a significant increase in free radical production, the free radicals must have interacted with NO and reduced the bioavailability of NO. Reduced NO bioavailability and oxidative stress resulted in endothelial dysfunction. The EDHF pathway was relatively resistant to mercury exposure, suggesting that there may be an upregulation of K⁺ _ATP channels in order to maintain circulation to compensate the attenuated NO-mediated vasodilatation (Figure 2).¹¹

Conclusion

Vascular endothelium is highly sensitive to oxidative stress, and this stress is the main cause of the endothelial dysfunction observed in CVDs such as hypertension and atherosclerosis.⁸⁸ The route, dose, and period of mercury exposure play an important role in determining its harmful effect on the vascular endothelium. Mercury produces a biphasic response in the VSM—vasorelaxation and vasoconstriction. It appears that a delicate balance exists between free radicals and NO released by ECs on mercury exposure. When there is an increase in NO release, enhanced endothelial function is observed. When the balance is tipped in favor of oxidative stress, endothelial dysfunction is observed. Therefore, NO-signaling mechanism and oxidative stress play an important function in the mercury-induced CVDs in the populations exposed to mercury.

Footnotes

Author Contribution

Swati Omanwar contributed to conception and design; contributed to acquisition and interpretation; drafted manuscript; and critically revised the manuscript. M. Fahim contributed to conception and revised the manuscript for important intellectual content. Both authors gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Salonen

Seppänen

Nyyssönen

. Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in eastern Finnish men. Circulation. 1995;91(3):645–655.

Virtanen

Voutilainen

Rissanen

. Mercury, fish oils, and risk of acute coronary events and cardiovascular disease, coronary heart disease, and all-cause mortality in men in eastern Finland. Arterioscler Thromb Vasc Biol. 2005;25(1):228–233.

Houston

. The role of mercury and cadmium heavy metals in vascular disease, hypertension, coronary heart disease, and myocardial infarction. Altern Ther Health Med. 2007;13(2):S128–S133.

Clarkson

Magos

Myers

. The toxicology of mercury—current exposures and clinical manifestations. N Engl J Med. 2003;349(18):1731–1737.

Sarkar

Bhan

. Mercury in the environment: effect on health and reproduction. Rev Environ Health. 2005;20(1):39–56.

Miller

Woods

. Urinary porphyrins as biological indicators of oxidative stress in the kidney. Interaction of mercury and cephaloridine. Biochem Pharmacol. 1993;46(12):2235–2241.

Huang

Cheng

Lin

. Lipid peroxidation in rats administrated with mercuric chloride. Biol Trace Elem Res. 1996;52(2):193–206.

Mahboob

Shireen

Atkinson

Khan

. Lipid peroxidation and antioxidant enzyme activity in different organs of mice exposed to low level of mercury. J Environ Sci Health B. 2001;36(5):687–697.

Reus

Bando

Andrés

Cascales

. Relationship between expression of HSP70 and metallothionein and oxidative stress during mercury chloride induced acute liver injury in rats. J Biochem Mol Toxicol. 2003;17(3):161–168.

10.

Chen

. Increased oxidative DNA damage, as assessed by urinary 8-hydroxy-2′-deoxyguanosine concentrations, and serum redox status in persons exposed to mercury. Clin Chem. 2005;51(4):759–767.

11.

Omanwar

Ravi

Fahim

. Persistence of EDHF pathway and impairment of the nitric oxide pathway after chronic mercury chloride exposure in rats: mechanisms of endothelial dysfunction. Hum Exp Toxicol. 2011;30(11):1777–1784.

12.

Golpon

Püchner

Barth

Welte

Wichert

Feddersen

. Nitric oxide-dependent vasorelaxation and endothelial cell damage caused by mercury chloride. Toxicology. 2003;192(2–3):179–188.

13.

da Cunha

Souza

Rossoni

França

Vassallo

. Effects of mercury on the isolated perfused rat tail vascular bed are endothelium-dependent. Arch Environ Contam Toxicol. 2000;39(1):124–130.

14.

Wiggers

Peçanha

Briones

. Low mercury concentrations cause oxidative stress and endothelial dysfunction in conductance and resistance arteries. Am J Physiol Heart Circ Physiol. 2008;295(3):33–43.

15.

Jalili

Abbasi

. Poisoning by ethyl mercury toluene sulphonanilide. Br J Ind Med. 1961;18:303–308.

16.

Eto

. Minamata disease. Neuropathology. 2000;20(suppl):S14–S19.

17.

Garcia

Gomez M

Boffetta

Caballero

Español

Gómez

Quintana J

. Cardiovascular mortality in mercury miners. Med Clin (Barc). 2007;128(20):766–771.

18.

Choi

Weihe

Budtz-Jorgensen

. Methylmercury exposure and adverse cardiovascular effects in Faroese whaling men. Environ Health Perspect. 2009;117(3):367–372.

19.

Trakhtenberg

. Chronic effects of mercury on organisms: the micromercurialism phenomenon on mercury handlers. 1974;Chap. VI:109–34, DHEW Publ. No. (NIH).

20.

Snodgrass

Sullivan

Rumack

. Mercury poisoning from home gold ore processing: use of penicillamine and dimercaprol. JAMA. 1981;246(17):1929–1931.

21.

Barregard

Sallsten

Jarvholm

. Mortality and cancer incidence in chloralkali workers exposed to inorganic mercury. Br J Ind Med. 1990;47(2):99–104.

22.

Boffetta

Sallsten

Garcia–Gomez

. Mortality from cardiovascular disease and exposure to inorganic mercury. Occup Environ Med. 2001;58(7):461–466.

23.

Siblerud

. The relationship between mercury from dental amalgam and the cardiovascular system. Sci Total Environ. 1990;99(1–2):23–36.

24.

Fagala

Wigg

. Psychiatric manifestations of mercury poisoning. J Am Acad Child Adolesc Psychiatry.1992;31(2):306–311.

25.

Goodrich

Wang

Gillespie

Werner

Franzblau

Basu

. Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals. Toxicol Appl Pharmacol. 2011;257(2):301–308.

26.

Valera

Dewailly

Poirier

. Association between methylmercury and cardiovascular risk factors in a native population of Quebec (Canada): a retrospective evaluation. Environ Res. 2013;120:102–108.

27.

Kim

Lee

Cha

Ahn

. Heavy metal as risk factor of cardiovascular disease—an analysis of blood lead and urinary mercury. J Prev Med Pub Health. 2005;38(4):401–407.

28.

Guallar

Sanz–Gallardo

Veer

. Mercury, fish oils, and the risk of myocardial infarction. N Engl J Med. 2002;347(22):1747–1754.

29.

Chan

Egeland

. Fish consumption, mercury exposure, and heart disease. Nutr Rev. 2004;62(2):68–72.

30.

Landmark

Aursnes

. Mercury, fish, fish oil and the risk of cardiovascular disease. Tidsskr Nor. Laegeforen. 2004;124(2):198–200.

31.

Hong

Cho

Park

Kim

Park

. Hair mercury level in smokers and its influence on blood pressure and lipid metabolism. Environ Toxicol Pharmacol. 2013;36(1):103–107.

32.

Valera

Dewailly

Poirier

Counil

Suhas

. Influence of mercury exposure on blood pressure, resting heart rate and heart rate variability in French Polynesians: a cross-sectional study. Environ Health. 2011;10:99.

33.

Eom

Choi

Ahn

. Reference levels of blood mercury and association with metabolic syndrome in Korean adults. Int Arch Occup Environ Health. 2014;87(5):501–513.

34.

Virtanen

Nyantika

Kauhanen

Voutilainen

Tuomainen

. Serum long-chain n-3 polyunsaturated fatty acids, methylmercury and blood pressure in an older population. Hypertens Res. 2012;35(10):1000–1004.

35.

Kalish

Rifas-Shiman

Wright

. Associations of prenatal maternal blood mercury concentrations with early and mid-childhood blood pressure: a prospective study. Environ Res. 2014;133:327–333.

36.

Périard

Beqiraj

Hayoz

. Associations of baroreflex sensitivity, heart rate variability, and initial orthostatic hypotension with prenatal and recent postnatal methylmercury exposure in the Seychelles Child Development Study at age 19 years. Int J Environ Res Public Health. 2015;12(3):3395–3405.

37.

Wakita

. Hypertension induced by methyl mercury in rats. Toxicol Appl Pharmacol. 2011;89(1):144–147.

38.

Carmignani

Finelli

Boscolo

. Mechanisms in cardiovascular regulation following chronic exposure of male rats to inorganic mercury. Toxicol Appl Pharmacol. 1983;69(3):442–450.

39.

Carmignani

Boscolo

Preziosi

. Renal ultrastructural alterations and cardiovascular functional changes in rats exposed to mercuric chloride. Arch Toxicol Suppl. 1989;13:353–356.

40.

Rossoni

Amaral

Vassallo

. Effects of mercury on the arterial blood pressure of anesthetized rats. Braz J Med Biol Res. 1999;32(8):989–997.

41.

da Cunha

Souza

Rossoni

França

Vassallo

. Effects of mercury on the isolated perfused rat tail vascular bed are endothelium-dependent. Arch Environ Contam Toxicol. 2000;39(1):124–130.

42.

Jindal

Garg

Mediratta

Fahim

. Protective role of melatonin in myocardial oxidative damage induced by mercury in murine model. Hum Exp Toxicol. 2011;30(10):1489–1500.

43.

Moreira

de Oliveira

Dutra

. Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease? Toxicol Sci. 2012;130(2):373–382.

44.

Skoczyńska

Poreba

Steinmentz-Beck

. The dependence between urinary mercury concentration and carotid arterial intima-media thickness in workers occupationally exposed to mercury vapour. Int J Occup Med Environ Health. 2009;22(2):135–142.

45.

Park

Lim

Chung

Kim

. Methylmercury-induced neurotoxicity in cerebral neuron culture is blocked by antioxidants and NMDA receptor antagonists. Neurotoxicology. 1996;17(1):37–45.

46.

Ganther

Goudie

Sunde

Kopecky

Wagner

. Selenium: relation to decreased toxicity of methylmercury added to diets containing tuna. Science. 1972;175(4026):1122–1124.

47.

Valera

Dewailly

Poirier

. ss. Hypertension. 2009;54(5):981–986.

48.

Yorifuji

Tsuda

Kashima

Takao

Harada

. Long-term exposure to methylmercury and its effects on hypertension in Minamata. Environ Res. 2010;110(1):40–46.

49.

Vupputuri

Longnecker

Daniels

Guo

Sandler

. Blood mercury level and blood pressure among US women: results from the National Health and Nutrition Examination Survey 1999-2000. Environ Res. 2005;97(2):195–200.

50.

Moszczyski

. Mercury and the risk of coronary heart disease. Przegl Lek. 2006;63(suppl 7):84–87.

51.

Virtanen

Rissanen

Voutilainen

Tuomainen

. Mercury as a risk factor for cardiovascular diseases. J Nutr Biochem. 2007;18(2):75–85.

52.

Wennberg

Strömberg

Bergdahl

. Myocardial infarction in relation to mercury and fatty acids from fish: a riskbenefit analysis based on pooled Finnish and Swedish data in men. Am J Clin Nutr. 2012;96(4):706–713.

53.

Virtanen

Laukkanen

Mursu

Voutilainen

Tuomainen

. Serum long-chain n-3 polyunsaturated fatty acids, mercury, and risk of sudden cardiac death in men: a prospective population-based study. PLoS One. 2012;7(7):e41046.

54.

McGuire

Ding

Triggle

. Endothelium-derived relaxing factors: a focus on endothelium-derived hyperpolarizing factor(s). Can J Physiol Pharmacol. 2001;79(6):443–470.

55.

Moncada

Rees

Schulz

Palmer

. Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci U S A. 1991;88(6):2166–2170.

56.

Forstermann

Closs

Pollock

. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension. 1994;23(6 pt 2):1121–1131.

57.

Michel

Feron

Sacks

Michel

. Reciprocal regulation of endothelial nitric-oxide synthase by Ca²⁺-calmodulin and caveolin. J Biol Chem. 1997;272(25):15583–1556.

58.

Feron

Saldana

Michel

. The endothelial nitric-oxide synthase-caveolin regulatory cycle. J Biol Chem. 1998;273(6):3125–3128.

59.

Ayajiki

Kindermann

Hecker

Fleming

Busse

. Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells. Circ Res. 1996;78(5):750–758.

60.

Rapoport

Murad

. Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP. Circ Res. 1983;52(3):352–357.

61.

Lincoln

Komalavilas

Cornwell

. Pleiotropic regulation of vascular smooth muscle tone by cyclic GMP-dependent protein kinase. Hypertension. 1994;23(6 pt 2):1141–1147.

62.

Bolotina

Najibi

Palacino

Pagano

Cohen

. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature. 1994;368(6474):850–853.

63.

Ignarro

Napoli

Loscalzo

. Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circ Res. 2002;90(1):21–28.

64.

Böhm

Pernow

. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res. 2007;76(1):8–18.

65.

Exton

. Regulation of Phospholipase D. Biochim Biophys Acta. 1999;1439(2):121–133.

66.

Natarajan

Garcia

. Agonist-induced activation of phospholipase D in bovine pulmonary artery endothelial cells: regulation by protein kinase C and calcium. J Lab Clin Med. 1993;121(2):337–347.

67.

Brindley

Waggoner

. Phosphatidate phosphohydrolase and signal transduction. Chem Phys Lipids. 1996;80(1–2):45–57.

68.

McGill

Ahmed

Christou

. Endothelial cells: role in infection and inflammation. World J Surg. 1998;22(2):171–178.

69.

Rubanyi

Vanhoutte

. Superoxide anions and hyperoxia inactivate EDRR. Am J Physiol. 1986;250(5 pt 2):H822–H827.

70.

Radi

Beckman

Bush

Freeman

. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys. 1991;288(2):481–487.

71.

Soloviev

Tishkin

Parshikov

Ivanova

Goncharov

Gurney

. Mechanisms of endothelial dysfunction after ionized radiation: selective impairment of the nitric oxide component of endothelium-dependent vasodilation. Br J Pharmacol. 2003;138(5):837–844.

72.

Torres

Rai

Hardiek

. Mercury intoxication and arterial hypertension: report of two patients and review of the literature. Pediatrics. 2000;105(3):E34.

73.

Omanwar

Saidullah

Ravi

Fahim

. Vasorelaxant effects of mercury on rat thoracic aorta: the nitric oxide signaling mechanism. Hum Exp Toxicol. 2013;33(9):904–910.

74.

Shimizu

Ishii

Yamamoto

Kawanishi

Momose

Kuroiwa

. Bradykinin induces generation of reactive oxygen species in bovine aortic endothelial cells. Res Commun Chem Pathol Pharmacol. 1994;84(3):301–14.

75.

Katusic

Vanhoutte

. Superoxide anion is an endothelium-derived contracting factor. Am J Physiol. 1989;257(1 pt 2):H33–H37.

76.

Suzuki

Ford

. Superoxide stimulates IP3-induced Ca²⁺ release from vascular smooth muscle sarcoplasmic reticulum. Am J Physiol. 1992;262(1 pt 2):H114–H116.

77.

Jin

Packer

Rhoades

. Reactive oxygen-mediated contraction in pulmonary arterial smooth muscle: cellular mechanisms. Can J Physiol Pharmacol. 1991;69(3):383–388.

78.

Stohs

Bagchi

. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 1995;18(2):321–336.

79.

Ercal

Gurer–Orhan

Aykin–Burns

. Toxic metals and oxidative stress part I: mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem. 2001;1(6):529–523.

80.

Pompella

Visvikis

Paolicchi

De Tata

Casini

. The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol. 2003;66(8):1499–1503.

81.

Wolf

Baynes

. Cadmium and mercury cause an oxidative stress-induced endothelial dysfunction. Biometals. 2007;20(1):73–81.

82.

Park

. Induction of reactive oxygen species and apoptosis in BEAS-2B cells by mercuric chloride. Toxicol In Vitro. 2007 Aug;21(5):789–94.

83.

Peltz

Sherwani

Kotha

. Calcium and calmodulin regulate mercury-induced phospholipase D activation in vascular endothelial cells. Int J Toxicol. 2009;28(3):190–206.

84.

Mazerik

Mikkilineni

Kuppusamy

. Mercury activates phospholipase a(2) and induces formation of arachidonic Acid metabolites in vascular endothelial cells. Toxicol Mech Methods. 2007;17(9):541–557.

85.

Lemos

Angeli

Jhuli K

. Low mercury concentration produces vasoconstriction, decreases nitric oxide bioavailability and increases oxidative stress in rat conductance artery. PLoS One. 2012;7(11):e49005.

86.

Rizzetti

Torres

Escobar

. Apocynin prevents vascular effects caused by chronic exposure to low concentrations of mercury. PLoS One. 2013;8(2):e55806.

87.

Harisa

Mariee

Abo-Salem

Attiaa

. Erythrocyte nitric oxide synthase as a surrogate marker for mercury-induced vascular damage: the modulatory effects of naringin. Environ Toxicol. 2014;29(11):1314–1322.

88.

Furchgott

Zawadzki

. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–6.

89.

Harisa

Alanazi

El-Bassat

Malik

Abdallah

. Protective effect of pravastatin against mercury induced vascular cells damage: erythrocytes as surrogate markers. Environ Toxicol Pharmacol. 2012;34(2):428–435.

90.

Omanwar

Saidullah

Ravi

Fahim

. Modulation of vasodilator response via the nitric oxide pathway after acute methyl mercury chloride exposure in rats. Biomed Res Int. 2013;2013:530603.

Mercury Exposure and Endothelial Dysfunction

Abstract

Keywords

Mercury and Its Association With Cardiovascular Disorders

Population Studies

Animal Studies

Physiological Role of Endothelium

Endothelial Dysfunction

Mercury Exposure, Oxidative Stress, and Vascular Endothelium

Mercury Exposure, Oxidative Stress, and NO Signaling

Conclusion

Footnotes

Author Contribution

Declaration of Conflicting Interests

Funding

References