This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/9/1392    most recent ATVBAHA.109.190082v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Messner, B. Articles by Bernhard, D. PubMed PubMed Citation Articles by Messner, B. Articles by Bernhard, D.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1392.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

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

Barbara Messner; Michael Knoflach; Andreas Seubert; Andreas Ritsch; Kristian Pfaller; Blair Henderson; Ying H. Shen; Iris Zeller; Johann Willeit; Günther Laufer; Georg Wick; Stefan Kiechl; David Bernhard

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.

Correspondence to PD Dr David Bernhard, Cardiac Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Ebene 8G09/07; Währinger Gürtel 18-20, A-1090, Vienna, Austria. 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.

Here we demonstrate that high cadmium (Cd) level is associated with increased intima-media thickness in 195 healthy young women, and that Cd causes endothelial damage and increases atherosclerotic plaque formation in mice. In vitro, physiological doses of Cd increase endothelial permeability by DNA damage-induced inhibition of endothelial proliferation and cell death induction, which is inhibited by zinc.

Key Words: cadmium, zinc • endothelial • dysfunction • injury • permeability • necrosis • ApoE • atherosclerosis • vascular • pathophysiology • risk factor • intima media thickness • apoptosis • cell death