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ToxSci Advance Access published online on November 17, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn236
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Arsenic and Cardiovascular Disease

J. Christopher States*,{dagger},1, Sanjay Srivastava{dagger},{ddagger}, Yu Chen§ and Aaron Barchowsky

* Department of Pharmacology & Toxicology {dagger} Center for Environmental Genomics and Integrative Biology {ddagger} Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292 § Departments of Environmental Medicine and Medicine, New York University School of Medicine, New York, NY 10016 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219

1 To whom correspondence should be addressed: J. Christopher States, Ph. D., Department of Pharmacology & Toxicology, University of Louisville, 570 S. Preston St., Suite 221, Lousiville, KY 40202, TEL: 502-852-5347, FAX: 502-852-2492, email: jcstates{at}louisville.edu

Received August 22, 2008; revision received October 15, 2008; accepted November 5, 2008


  Abstract

Chronic arsenic exposure is a world wide health problem. Although arsenic induced cancer has been widely studied, comparatively little attention has been paid to arsenic induced vascular disease. Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease. In addition, studies suggest that susceptibility to arsenic induced vascular disease may be modified by nutritional factors in addition to genetic factors. Recently, animal models for arsenic induced atherosclerosis and liver sinusoidal endothelial cell dysfunction have been developed. Initial studies in these models show that arsenic exposure accelerates and exacerbates atherosclerosis in ApoE-knockout mice. Microarray studies of liver mRNA and micoRNA abundance in mice exposed in utero suggest that a permanent state of stress is induced by the arsenic exposure. Furthermore, the livers of the arsenic exposed mice have activated pathways involved in immune responses suggesting a pro-hyperinflammatory state. Arsenic exposure of mice after weaning show a clear dose response in the extent of disease exacerbation. In addition, increased inflammation in arterial wall is evident. In response to arsenic stimulated oxidative signaling, liver sinusoidal endothelium differentiates into a continuous endothelium that limits nutrient exchange and waste elimination. Data suggest that NADPH oxidase derived superoxide or its derivatives are essential second messengers in the signaling pathway for arsenic-stimulated vessel remodeling. The recent findings provide future directions for research into the cardiovascular effects of arsenic exposure.

Key Words: arsenic; inflammation; oxidative signaling; vascular disease; nutrition; microarray.

Author email addresses: Aaron Barchowsky: aab20{at}pitt.edu, Yu Chen: Y.Chen{at}nyu.edu, Sanjay Srivastava: sanjay{at}louisville.edu


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