Cadmium Is a Novel and Independent Risk Factor for Early Atherosclerosis Mechanisms and In Vivo Relevance

Abstract

Objectives-Although cadmium (Cd) is an important and common environmental pollutant and has been linked to cardiovascular diseases, little is known about its effects in initial stages of atherosclerosis. Methods and Results-In the 195 young healthy women of the Atherosclerosis Risk Factors in Female Youngsters(ARFY) study, cadmium (Cd) level was independently associated with early atherosclerotic vessel wall thickening (intima-media thickness exceeding the 90th percentile of the distribution; multivariable OR 1.6[1.1.-2.3], Pϭ0.016). In line, Cd-fed ApoE knockout mice yielded a significantly increased aortic plaque surface compared to controls (9.5 versus 26.0 mm 2 , PϽ0.004). In vitro results indicate that physiological doses of Cd increase vascular endothelial permeability up to 6-fold by (1) inhibition of endothelial cell proliferation, and (2) induction of a caspase-independent but Bcl-xL-inhibitable form of cell death more than 72 hours after Cd addition. Both phenomena are preceded by Cd-induced DNA strand breaks and a cellular DNA damage response. Zinc showed a potent protective effect against deleterious effects of Cd both in the in vitro and human studies. Conclusion-Our research suggests Cd has promoting effects on early human and murine atherosclerosis, which were partly offset by high Zn concentrations. Key Words: cadmium, zinc Ⅲ endothelial Ⅲ dysfunction Ⅲ injury Ⅲ permeability Ⅲ necrosis Ⅲ ApoE Ⅲ atherosclerosis Ⅲ vascular Ⅲ pathophysiology Ⅲ risk factor Ⅲ intima media thickness Ⅲ apoptosis Ⅲ cell death S ince the use of Cd in manifold industrial applications, sources for and the amount of Cd uptake by humans has increased dramatically. Cd is, for example, released into the air through the burning of fossil fuels (coal, oil) and the incineration of municipal waste (Environmental Protection Agency, 2000). The most relevant sources for Cd uptake by humans are, however, cigarette smoking (one cigarette contains Ϸ1 to 2 g; daily uptake of Cd Ϸ1 to 3 g per pack smoked) and food for nonsmokers (daily intake Ϸ30 g; daily uptake Ϸ1 to 3 g), as well as exhaust gases (Agency for Toxic Substances and Disease Registry, 1999). After inhalation or ingestion of Cd, it is transferred into the bloodstream (whole blood and serum Cd concentrations range between Ϸ0.2 and Ϸ20 nmol/L 1,2 ), where Cd is transported either as a free ion or protein-bound, eg, attached to albumin or metallothioneins. Cd is taken up by cells of Cd target organs (liver, kidneys, and testis) via solute carriers, calcium and manganese channels, and iron transporters. [3][4][5] In 2001, Abu-Hayyeh et al 6 demonstrated that the aortic vessel wall is another under-recognized target organ for Cd accumulation (aortic wall concentrations of Cd are up to 20 mol/ L). Epidemiologically, high Cd level was found to be associated with hypertension, stroke, and cardiac arrest, 7-9 but confirmatory data are sparse and the mechanistic basis for these interactions remains unclear. Houtman et al observed a higher than expected frequency of atherosclerosis in a...

Plasma Concentrations of Some Trace Element and Heavy Metals in Patients with Metastatic Colon Cancer

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Cadmium exposure in the population: from health risks to strategies of prevention

“…Chronic exposure to Cd not only leads to its accumulation in the kidneys and liver but also in the endothelium and vascular smooth muscle cells (Messner and Bernhard 2010;Messner et al 2009). …”

“…This non-invasive measure is useful in assessing the patency of the leg arteries and predicts cardiovascular morbidity and mortality (Resnick et al 2004). After accounting for traditional cardiovascular risk factors, the odds ratio of peripheral arterial disease showed significant increase in the odds 2.82 (95% CI 1.36-5.85) for the highest blood Cd quartile ([6.23 nmol/l or 0.70 lg/l) compared with the lowest quartile (B3.56 nmol/l or 0.40 lg/l) (Navas-Acien et al (Messner et al 2009). In contrast to these studies the Belgian populations did not show correlations between measures of arterial function and blood Cd and failed to confirm that increased Cd body burden (determined by 24-h urinary Cd excretion) was associated with decreased arterial function (Schutte et al 2008a;Plusquin et al 2005).…”

Some mineral, trace element and heavy metal concentrations in newborns with esophageal atresia and their mothers

“…The Pb is a toxic and carcinogenic metal [11,12]. An important decrease was detected in Pb level compared to the control group (p<0.01).…”

“…Cadmium's industrial access arises from its matchless properties [11]. As a consequence, Cd increases enhanced lipid peroxidation and DNA damage; on the other hand decreases marked disturbances of antioxidant defense system [6,19].…”