ToxSci Advance Access originally published online on October 25, 2006
Toxicological Sciences 2007 95(2):485-494; doi:10.1093/toxsci/kfl145
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Gasoline Exhaust Emissions Induce Vascular Remodeling Pathways Involved in Atherosclerosis
* Division of Toxicology, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, New Mexico 87108
Division of Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawai'i
1 To whom correspondence should be addressed. Fax: (505) 348-4980. E-mail: mcampen{at}lrri.org.
Received August 18, 2006; accepted October 20, 2006
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Abstract |
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Epidemiological evidence indicates that environmental air pollutants are positively associated with the development of chronic vascular disease; however, the mechanisms involved have not been fully elucidated. In the present study we examined molecular pathways associated with chronic vascular disease in atherosclerosis-prone apolipoprotein E–deficient (ApoE–/–) mice, including markers of vascular remodeling and oxidative stress, in response to exposure to the ubiquitous environmental pollutant, gasoline engine emissions. ApoE–/– mice, on a high-fat diet, were exposed by inhalation to either filtered air; 8, 40, or 60 µg/m3 particulate matter whole exhaust; or filtered exhaust with gases matching the 60-µg/m3 concentration, for 7 weeks. Aortas and plasma were collected and assayed for changes in histochemical markers, real-time reverse transcriptase–polymerase chain reaction, and indicators of oxidative damage. Inhalational exposure to gasoline engine emissions resulted in increased aortic mRNA expression of matrix metalloproteinase-3 (MMP-3), MMP-7, and MMP-9, tissue inhibitor of metalloproteinases-2, endothelin-1 and heme oxygenase-1 in ApoE–/– mice; increased aortic MMP-9 protein levels were confirmed through immunohistochemistry. Elevated reactive oxygen species were also observed in arteries from exposed animals, despite absence of plasma markers. Similar findings were also observed in the aortas of ApoE–/– mice exposed to particle-filtered atmosphere, implicating the gaseous components of the whole exhaust in mediating the expression of markers associated with the vasculopathy. These findings demonstrate that exposure to gasoline engine emissions results in the transcriptional upregulation of factors associated with vascular remodeling, as well as increased markers of vascular oxidative stress, which may contribute to the progression of atherosclerosis and reduced stability of vulnerable plaques.
Key Words: atherosclerosis; matrix metalloproteinases; reactive oxygen species; particulate matter; endothelin-1.