The goal of this application is to engage a multidisciplinary team of leading environmental, cardiovascular and proteomics researchers in the study of the pro-oxidative and pro-inflammatory pathways by which ambient pariculate matter (PM) enhance atherogenesis in apolipoprotein (apoE) and LDL receptor (LDL-R) deficient mice. The principal hypothesis is that PM-induced oxidative stress synergizes with oxidized lipid components to enhance inflammation and apoptosis in atherosclerotic lesions. There are three specific aims.
Aim 1 will determine whether ambient PM exposures exacerbate atherosclerosis in these genetically susceptible strains. Animals will be exposed to ambient ultrafine (aerodynamic diameter < 0.1 mu m) and fine (< 2.5 mu m) particulates collected by particle concentrators in the Los Angeles basin. The endpoints will be a quantitative assessment of early and late atherosclerotic lesion development. These studies will be supplemented by in vivo and in vitro studies looking at the pro-oxidative, pro-inflammatory, and pro-apoptotic effects of concentrated ambient particulates (CAPs) on vascular endothelial, smooth muscle and phagocytic cells.
Aim 2 will determine the role of PM-induced oxidative stress in inflammation and apoptosis. Aortic vascular tissue from CAPs exposed animals will be examined for lipid peroxidation and for heme oxygenase 1 (HO-1) expression, MAP kinase activation, and apoptosis. Blood will be used to study CAPs effects on acute phase proteins, fibrinogen and oxidative modification of protective HDL activity. Transgenic HO-1 promoter-luciferase mice will be used for in vivo imaging of the kinetics and vascular sites of oxidative stress generation. In vitro studies will include proteome analysis of the oxidative stress response in endothelial cells. All oxidative stress effects will be correlated with the PAH and quinone content of the CAPs, as well as their in vitro redox cycle capacity, determined by the DTT assay.
Aim 3 will determine whether modified antioxidant defense mechanisms affect the induction of atherosclerotic lesions by CAPs in apoE deficient mice, which have been crossed with HO-1 transgenic as well as paraoxonase knockout animals. The investigators will also determine whether a deficiency of the Nrf-2 transcription factor, which regulates antioxidant enzyme expression, will affect lesion development in apoE t/- animals. These mice will be exposed to CAPs as discussed in Aims 1 and 2, and select endpoints used to demonstrate the effect on atherosclerotic inflammation and apoptosis.
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