MT COBRE: MECHANISM OF CARDIOVASCULAR DISEASE FROM ARSENIC EXPOSURE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 砷广泛分布在地壳中，通过采矿、冶炼、制造和农药使用等人类活动释放到空气、土壤和水中。流行病学研究表明，接触饮用水中的砷会增加心血管疾病的死亡风险。摄入砷会导致活性氧和氮的产生，从而改变血管壁的生理。这些改变可能导致动脉粥样硬化的恶化，动脉粥样硬化是其他心血管疾病的主要诱因。本项目的总体目标是在砷促进动脉粥样硬化发展的假设下，确定砷诱导动脉粥样硬化的机制和调控途径。将通过在发生临床动脉粥样硬化的小鼠模型(apoE-/-LDLR-/-)中确定动脉粥样硬化的发生和发展来研究砷增加心血管疾病发病率和死亡率的可能性。除了小鼠模型外，牛和人的主动脉内皮细胞将被用来研究内皮细胞的分子变化，内皮细胞是动脉粥样硬化形成开始的细胞层。具体研究将评估砷对以下方面的影响：(1)内皮细胞中活性物质的形成；(2)内皮细胞和动脉粥样硬化小鼠模型中关键致动脉粥样硬化调节分子的表达；(3)小鼠模型中动脉粥样硬化的发展。这些研究将为确定与砷暴露相关的健康风险和潜在的心血管疾病预防策略提供重要数据。

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 earths 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.