Arsenic exposure exacerbates atherosclerotic plaque formation and increases nitrotyrosine and leukotriene biosynthesis.
A correlation between arsenic and cardiovascular disease (CVD) has been established through epidemiological studies, although the mechanisms are unknown. Using a mouse model that develops atherosclerotic lesions on a normal chow diet, we have confirmed a connection between long-term arsenic intake and CVD. Our results reveal a significant increase in the degree of atherosclerotic plaque stenosis within the innominate artery of ApoE-/-/LDLr-/- mice treated with 10 ppm sodium arsenite (133 microM) in drinking water for 18 weeks compared to controls. Immunohistochemistry shows nitrotyrosine formation, a marker of reactive nitrogen species generation, is significantly higher within the atherosclerotic plaque of arsenic-treated mice. In addition, there is a significant increase in the 5-lipoxygenase (5-LO) product, leukotriene E4 (LTE4), in the serum of arsenic-treated mice. This is supported by induction of the 5-LO protein and subsequent increases in LTE4 synthesis in bovine aortic endothelial cells. This increase in LTE4 is partially inhibited by inhibitors of nitric oxide synthase, suggesting a link between reactive nitrogen species and arsenic-induced inflammation. Furthermore, there is a significant increase in prostacyclin (PGI2) in the serum of arsenic-treated mice. We conclude that changes in specific inflammatory mediators such as LTE4 and PGI2 are related to arsenic-induced atherosclerosis. In addition, amplified synthesis of reactive species such as peroxynitrite results in increased protein nitration in response to arsenic exposure. This finding is consistent with the pathology seen in human atherosclerotic plaques.
Bunderson
Melisa
M
Center for Environmental Health Sciences, University of Montana, Missoula, MT 59812-1552, USA.
Brooks
Diane M
DM
Walker
David L
DL
Rosenfeld
Michael E
ME
Coffin
J Douglas
JD
Beall
Howard D
HD
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis; D018053:Arsenites / Q000633:toxicity*; D001161:Arteriosclerosis / Q000139:chemically induced* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D017999:Leukotriene E4 / Q000096:biosynthesis* / Q000097:blood; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D017670:Sodium Compounds / Q000633:toxicity*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis*
D018053:Arsenites; D004791:Enzyme Inhibitors; D017670:Sodium Compounds; C002744:3-nitrotyrosine; D014443:Tyrosine; C017947:sodium arsenite; D017999:Leukotriene E4; D001094:Arachidonate 5-Lipoxygenase