Proteomic determination of arsenical action

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DESCRIPTION (provided by applicant): The cardiovascular diseases caused by As(lll)-compounds, such as hypertension, peripheral vascular disease, and ischemic heart disease, share common components of vascular remodeling and inappropriate proliferative responses in the vessel walls. Sub-chronic (ca. 5 weeks) exposures of mice to low levels of arsenic in drinking water enhanced neovascularization of Matrigel implants and differentially affected cardiac angiogenic gene expression. While these effects are known for inorganic arsenic, precious little is known regarding the effects of widely used agricultural organic arsenic compounds. This proposal focuses on defining mechanisms for the toxic effects of 3-nitro-4-hydroxy phenyl arsonic acid (roxarsone) in the vasculature. There are two specific aims of the proposed research: 1) to investigate the role of roxarsone and related aromatic arsenic compounds in promoting angiogenesis. This will be tested in a novel mouse embryonic stem cell assay that measures vessel development in Matrigel. 2) To use a novel proteomic approach to investigate the transient effects of arsenic and arsenicals on cell signaling proteins. We will use new chemical labeling methods, 2-dimensional protein separation, and matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) to identify proteins that are either differentially expressed, post-translationally modified, or directly bound to arsenicals when vascular smooth muscle cells are exposed to low, environmentally relevant levels of arsenic or roxarsone. These studies will greatly expand the understanding of the biochemical activation of vascular cell signaling that is relevant to arsenic-related vascular diseases.