ToxSci Advance Access originally published online on January 30, 2009
Toxicological Sciences 2009 111(1):80-88; doi:10.1093/toxsci/kfp004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ambient Particulates Alter Vascular Function through Induction of Reactive Oxygen and Nitrogen Species
* Davis Heart & Lung Research Institute, Ohio State University, Columbus, Ohio 43210
New York University School of Medicine, Tuxedo, New York 10987
1 To whom correspondence should be addressed at 460 W. 12th Avenue Room 398, Biomedical Research Tower, Ohio State University, Columbus, OH 43210-1252. Fax: (614) 688-4233. E-mail: Sanjay.Rajagopalan{at}osumc.edu.
Received September 29, 2008; accepted January 9, 2009
 |
Abstract |
|---|
Previous studies have shown a link between inhaled particulate matter (PM) exposure in urban areas and susceptibility to cardiovascular diseases. Although an oxidative stress pathway is strongly implicated, the locus of generation of reactive oxygen species (ROS) and the mechanisms by which these radicals exert their effects remain to be characterized. To test the hypothesis that exposure to environmentally relevant inhaled concentrated ambient PM (CAPs) enhances atherosclerosis through induction of vascular ROS and reactive nitrogen species. High-fat chow fed apolipoprotein E–/– mice were exposed to CAPs of less than 2.5 µm (PM2.5) or filtered air (FA), for 6 h/day, 5 days/week, for 4 months in Manhattan, NY. Atherosclerotic lesions were analyzed by histomorphometricly. Vascular reactivity, superoxide generation, mRNA expression of NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase subunits, inducible nitric oxide synthase, endothelial nitric oxide synthase, and GTP cyclohydrolase I were also assessed. Manhattan PM2.5 CAPs were characterized by higher concentrations of organic and elemental carbon. Analysis of vascular responses revealed significantly decreased phenylephrine constriction in CAPs-exposed mice, which was restored by a soluble guanine cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. Vascular relaxation to A23187 [GenBank] , but not to acetylcholine, was attenuated in CAPs mice. Aortic expression of NADPH oxidase subunits (p47phox and rac1) and iNOS were markedly increased, paralleled by increases in superoxide generation and extensive protein nitration in the aorta. The composite plaque area of thoracic aorta was significantly increased with pronounced macrophage infiltration and lipid deposition in the CAPs mice. CAPs exposure in Manhattan alters vasomotor tone and enhances atherosclerosis through NADPH oxidase dependent pathways.
Key Words: air pollution; PM2.5; CAPs; ApoE–/– mice; atherosclerosis; reactive oxygen species; reactive nitrogen species.