Although epidemiological studies have shown a clear link between pollution and cardiovascular events, the pathophysiologic mechanisms remain poorly characterized. There is emerging evidence that particulate components of air pollution (PM10 as well as PM2.5) may mediate organ toxicity through generation of reactive oxygen species (ROS). Since pollution mediated adverse cardiovascular outcomes seem to preferentially target at-risk patient populations with pre-existing risk factors and established cardiovascular diseases (all associated with heightened oxidant stress), studies of pollution exposure in susceptible animal models is likely to provide realistic insights into relevant pathologic mechanisms. The overall hypothesis of this study is that long-term exposure to environmentally relevant concentrations of concentrated airborne particulate substances (CAPS) plays a fundamental role in the initiation and progression of atherosclerosis in a genetically susceptible model (Apo E-/-) through the activation of ROS dependent pathways. In the first specific aim, the investigators hypothesize that sub-acute exposure to CAPS results in early deterioration in endothelial function through the generation of superoxide in the vessel wall, that results in the inactivation of bio-available nitric oxide. This will be accomplished by studying the effects of a sub-acute (6-week) exposure to CAPS on endothelium dependent responses, free-radical sources in the vasculature and investigating the effects of CAPS on nitric oxide synthase activity and cGMP levels in the vessel wall. In the second specific aim they will elucidate the effects of sub-acute (6 week) and chronic (20 week) CAPS exposure on vascular inflammation and atherosclerosis using histochemical, immunohistochemical and magnetic resonance microscopy (MRM) approaches. In the final specific aim, the investigators will investigate potential mechanisms through which CAPS may modulate eNOS function in the vessel wall and will evaluate the effect of CAP on the eNOS cofactor vascular 6R-5,6,7,8-tetrahydrobiopterin (BH4) and its oxidized analogs [7,8 dihydrobiopterin (BH2) and biopterin] in arterial segments derived from Apo E-/- exposed to CAPS. Principal component analysis will be performed to elucidate which source-related components are most closely associated with biological responses in specific aims 1 and 2. This study is expected to provide a firm linkage between CAPS exposure and atherosclerosis progression and will provide a pathophysiologic basis for the adverse cardiovascular effects of CAPS.
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