on June 25, 2009
Published online before print June 25, 2009, doi: 10.1161/ATVBAHA.109.190082
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Submitted on April 23, 2009
Accepted on June 10, 2009
Cadmium Is a Novel and Independent Risk Factor for Early Atherosclerosis Mechanisms and In Vivo Relevance
Barbara Messner ;
From the Cardiac Surgery Research Laboratory, Department of Cardiac Surgery (B.M., I.Z., G.L., D.B.), the Departments of Neurology (M.K., J.W., S.K.) and Medicine (A.R.), and the Division of Histology and Embryology (K.P.), Innsbruck Medical University, Austria; the Department of Chemistry (A.S.), Philipps-University of Marburg, Germany; the Laboratory of Autoimmunity (B.H., G.W.), Biocenter, Innsbruck, Austria; the Department of Surgery (Y.H.S.), Baylor College of Medicine, Houston, Tex; and Cardiothoracic Surgery, Department of Surgery (G.L.), Medical University of Vienna, Austria.
* To whom correspondence should be addressed. E-mail: David.Bernhard{at}i-med.ac.at.
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], P=0.016). In line, Cd-fed ApoE knockout mice yielded a significantly increased aortic plaque surface compared to controls (9.5 versus 26.0 mm2, P<0.004). 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 • endothelial • dysfunction • injury • permeability • necrosis • ApoE • atherosclerosis • vascular • pathophysiology • risk factor • intima media thickness • apoptosis • cell death