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Final Progress Reports: Dartmouth College: Induction of Oxidative Stress and Activation of Transcription Factors by Toxic Metals

Superfund Research Program

Induction of Oxidative Stress and Activation of Transcription Factors by Toxic Metals

Project Leader: Aaron Barchowsky (University of Pittsburgh)
Grant Number: P42ES007373
Funding Period: 1995 - 2000

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Final Progress Reports

Year:   1999 

Though drinking-water arsenic is associated with increased incidence of occlusive vascular diseases, the mechanisms through which arsenic, especially in its most toxic form, arsenic(III) (arsenite), promotes this narrowing of blood vessels are relatively unknown. The working hypothesis of Project 1 is that arsenite stimulates reactive oxygen production in the membranes of the endothelial and smooth muscle cells, causing inward expansion of the blood vessels. It was demonstrated that exposure to low levels of arsenite increases reactive oxygen formation by vascular endothelial cells, decreasing the release of vessel dilators and initiating cell signaling, which promotes growth in the endothelial and vascular smooth muscle cells. Higher concentrations of arsenite activated the stress-induced signaling pathways associated with cell death. Arsenite did not increase release of the vasodilator nitric oxide from endothelial cells and prevented its release in response to proteins that dilate blood vessels. NADPH oxidase residing on the surface of endothelial cells was identified as the primary mediator of arsenite-stimulated cell signaling. Low levels of arsenite were shown to directly activate NADPH oxidase. Inhibitors of the oxidase blocked this activation by arsenite. Higher levels of arsenite begin to decrease the activity of the enzyme, suggesting that this enzyme is the source of oxidants that promote cell proliferation, but not the source of oxidants that cause cell death. Future studies are aimed at identifying the cellular switch that arsenite uses to activate NADPH oxidase and investigating how this switch affects the proliferative endothelial cell phenotype. These studies will improve the understanding of how low arsenite exposure causes vascular disease and will also provide fundamental insight into mechanisms for arsenite-induced signaling that could lead to other proliferative diseases, such as cancer. Project 1 also investigated the effects of chromium(VI) on expression of proteins in the fibrinolytic cascade and on mechanisms for suppressing of gene transcription in the human lung airway epithelial cells. The purpose of these studies was to resolve mechanisms through which inhaled chromium(VI) causes fibrosis and emphysema-like disease in the lung. These studies demonstrated that chromium(VI) inhibited both the synthesis and activity of urokinase-type plasminogen activator, the key enzyme that initiates fibrinolysis to prevent scarring. In addition, chromium(VI) caused competition between transcription factors for their co-factors. This competition reduces activity of protective transcription factors to produce cells that are more susceptible to killing by normally non-lethal inflammatory stimuli.

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