ROLE OF SODIUM ARSENITE IN ATHEROGENESIS By

Epidemiological studies as well as controlled animal studies have associated exposure to arsenic through drinking water with the development of atherosclerosis. In this study, we have shown for the first time that low and environmentally relevant concentrations of arsenic accelerate atherogenesis. The objective of this study was to elucidate the mechanisms of arsenic-induced atherosclerosis by (1) characterizing the time- and concentration-dependent effects of sodium arsenite [As(III)] on the development of atherosclerosis in ApoE-/- /LDLr-/- mice, (2) determining whether As(III)-induced peroxynitrite activates protein kinase C (PKC) isotypes, α and β, in human aortic endothelial cells (HAECs) and (3) determining the effects of activation of PKC isotypes, α and β, on the endothelial barrier. Accordingly, exposure of ApoE-/- /LDLr-/- mice to As(III) in drinking water showed an increasing trend in atherosclerotic plaque formation in as early as 5 weeks within the innominate arteries. Most remarkable was the evidence that environmentally relevant concentrations of As(III) resulted in significant increase in plaque formation. Initiation of atherosclerosis results from activation/dysfunction of the vascular endothelium that maintains a semipermeable barrier between the blood an