MT COBRE: MECHANISM OF CARDIOVASCULAR DISEASE FROM ARSENIC EXPOSURE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Arsenic is widely dispersed in the earth¿s crust and is released into the air, soil and water by human activities such as mining, smelting, manufacturing and pesticide application. Epidemiological studies suggest that exposure to arsenic in drinking water increases the risk of mortality from cardiovascular disease. Ingestion of arsenic causes production of reactive oxygen and nitrogen species that can alter the physiology of the vessel wall. These alterations could lead to exacerbation of atherosclerosis, the primary contributor to other cardiovascular diseases. The overall objective of this project is to identify the mechanisms and regulatory pathways involved in arsenic-induced atherosclerosis with the hypothesis that arsenic facilitates development of atherosclerosis. The potential for arsenic to increase morbidity and mortality from cardiovascular disease will be investigated by determining onset and progression of atherosclerosis in a mouse model (apoE-/-LDLR-/-) that develops clinical atherosclerosis. In addition to the mouse model, bovine and human aortic endothelial cells will be used to study molecular changes in the endothelium, the layer of cells where atherogenesis begins. Specific studies will evaluate the effects of arsenic on (1) formation of reactive species in endothelial cells, (2) expression of key atherogenic regulatory molecules in endothelial cells and the atherosclerotic mouse model and (3) development of atherosclerosis in the mouse model. These studies will provide important data for determination of health risks associated with arsenic exposure and potential cardiovascular disease prevention strategies.