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Mechanisms of the Exacerbation of Atherosclerosis by Semi-Volatile Organic Constituents of Inhaled Ambient Particulate Matter in apoE -/- Mice

  • Author(s): Keebaugh, Andrew James
  • Advisor(s): Phalen, Robert F
  • Kleinman, Michael T
  • et al.
Abstract

Emissions-related particulate matter exposures are thought to be associated with thousands of excess deaths per year, many of which are related to cardiovascular disease. Ultrafine particles contain a large proportion of redox-active organic compounds that can exist in either the vapor or particle phase and are considered SVOCs. After inhalation, these compounds may be responsible for initiating a cascade of oxidative stress and inflammation in the body that can promote atherosclerotic plaque development that can lead to CAD. The goal of this project was to investigate the mechanisms of how exposure to particle associated SVOCs promotes atherosclerosis. ApoE -/- mice, which are prone to developing atherosclerosis, were exposed to unmodified UF CAPs, deCAPs with the SVOC components removed by a thermodenuder, or adjCAPs that was adjusted to match the concentration of deCAPs. Mice were exposed for nine weeks for five hours per day, four days per week at the UC Irvine campus. A control group was exposed to purified, filtered air. A higher percentage of mice exposed to adjCAPs formed arterial plaques compared to deCAPs and air exposed mice. Furthermore there was greater vascular wall thickening and fibrosis in the arteries of mice exposed to CAPs compared to deCAPs. IL-6 was increased in the serum of mice exposed to adjCAPs relative to deCAPs, indicating that the SVOCs are promoting atherosclerosis through a pro-inflammatory mechanism. Furthermore, adjCAPs exposure increased the ratio of LDL to HDL cholesterol, so SVOCs may be related to pro-atherogenic alterations to lipid metabolism. The power in the high frequency component of HRV, a measure of cardiac parasympathetic activity, was acutely reduced in mice exposed to CAPs, and daily changes in HF HRV were associated with the O:C ratio of the UF fraction of CAPs. These associations implicated POA, which comprises a major component of SVOCs, as potentially driving the toxic effects. The attenuation of atherosclerostic plaque formation with deCAPs exposure indicates that SVOCs in CAPs exposures are important contributors to toxic cardiovascular effects and these components deserve consideration in discussions of regulation of primary PM emissions and human exposure reduction strategies to protect public health.

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