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Abstract

Grant Number:	5P42ES007373-100008
Project Title:	Mechanism of arsenic induced vascular disease

PI Information:	Name	Email	Title
	BARCHOWSKY, AARON	aab20@pitt.edu	ASSOCIATE PROFESSOR

Abstract: The primary objective of the proposed studies is to define the cellular and molecular mechanisms responsible for changes in vascular cell phenotype and proliferation, which promote occlusive cardiovascular disease following exposure to low levels of arsenite. The hypothesis for these studies is that arsenite causes vascular disease by stimulating oxidant- mediated signaling in endothelial and smooth muscle cells. In addition the oxidants caused by arsenite exposure may deprive the vasculature of nitric oxide required for vasodilation and suppression of smooth muscle cell proliferation. Studies in the first funding period made the distinction between oxidant-sensitive cell regulation and oxidant stress in response to increasing amounts of arsenite. Low, environmentally relevant levels of arsenite and oxidants were shown to be regulatory and proliferative, while high levels activate stress pathways and cell death. The proposed studies will continue to use primary endothelial and smooth muscle cells to define the source of arsenite-stimulated reactive oxygen and the downstream signals that promote phenotypic change and proliferation. Focus will be on the signal cascades that initiate superoxide production by NAD(P)H oxidase. Dominant negative strategies, with highly expressed adenoviral vectors, will demonstrate the role of the monomeric GTPase, Rac1, in initiating this activity and in promoting the activation NF-B, an oxidant-sensitive transcription factor that promotes expression of cytoprotective genes and cell proliferation. Finally, mice will be chronically exposed to low levels of arsenite to test the hypothesis that arsenite decreases vasodilator-induced nitric oxide release and promotes NF-B dependent thickening of brain blood vessels. These studies will be facilitated by in vivo electron paramagnetic resonance spectroscopy and an adenoviral construct that suppresses NF-B activation.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
arsenic, environmental toxicology, hazardous substance, pathologic process, vascular endothelium
biological signal transduction, cell proliferation, environmental exposure, gene environment interaction, nitric oxide, oxidative stress, phenotype, toxin metabolism
laboratory mouse

Institution:	DARTMOUTH COLLEGE
	Office of Sponsored Projects
	HANOVER, NH 03755
Fiscal Year:	2004
Department:
Project Start:
Project End:
ICD:	NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
IRG:	ZES1

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