Arsenic exposure accelerates atherogenesis in apolipoprotein E(-/-) mice.
Epidemiologic studies have shown an association between elevated arsenic levels in drinking water and an increased risk of atherosclerosis and vascular diseases. The studies presented here were performed to evaluate the atherogenic potential of arsenic using a well-established and controlled animal model of human atherosclerosis, mice deficient in apolipoprotein E (ApoE), and in vitro systems including primary human vascular cells. Wild-type and ApoE-deficient mice were exposed to 20 or 100 microg/mL sodium arsenite in drinking water for 24 weeks. As assessed morphometrically, the size of grossly discernible lesions covering the intimal area of aorta were increased significantly in arsenic-treated ApoE-deficient mice compared with nontreated transgenic mice. This effect was not associated with increased levels of serum cholesterol but was accompanied by an accumulation of arsenic in the vessel wall. Introduction of cocoa butter into the diet for 2 weeks resulted in higher serum cholesterol levels and only slight increases in the lesion size in control or arsenic-exposed ApoE-deficient mice. There were no lesions observed in the wild-type C57BL6 mice, resistant to atherosclerosis, whether they received arsenic or control drinking water. In vitro studies, including primary aorta endothelial or smooth muscle cells, were conducted to evaluate whether arsenic induces cellular mechanisms relevant to atherogenesis such as endothelial dysfunction, lipid oxidation, and smooth muscle cell proliferation. Arsenic treatment does not modulate endothelial cell-mediated lipid oxidation or smooth muscle cell proliferation but induced the expression of genes coding inflammatory mediators, including interleukin-8. Induction of endothelial inflammatory activity may play a role in arsenic-related vascular effects.
Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA. psimeonova@cdc.gov
Petia P
PP
Simeonova
Tracy
T
Hulderman
Dan
D
Harki
Michael I
MI
Luster
D000818:Animals; D001057:Apolipoproteins E / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D001151:Arsenic / Q000633:toxicity*; D020261:Arsenic Poisoning / Q000150:complications*; D001161:Arteriosclerosis / Q000503:physiopathology*; D002319:Cardiovascular System / Q000166:cytology; D018929:Cell Culture Techniques; D002455:Cell Division; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000096:biosynthesis; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000166:cytology
D001057:Apolipoproteins E; D016209:Interleukin-8; D001151:Arsenic