Title: Ambient particulates alter vascular function through induction of reactive oxygen and nitrogen species.
Authors: Ying, Zhekang; Kampfrath, Thomas; Thurston, George; Farrar, Britten; Lippmann, Mort; Wang, Aixia; Sun, Qinghua; Chen, Lung Chi; Rajagopalan, Sanjay
Published In Toxicol Sci, (2009 Sep)
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 microm (PM(2.5)) 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 PM(2.5) 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, but not to acetylcholine, was attenuated in CAPs mice. Aortic expression of NADPH oxidase subunits (p47(phox) 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.
PubMed ID: 19182107
MeSH Terms: Animals; Apolipoproteins E/genetics; Atherosclerosis/pathology; Blood Vessels/drug effects*; Blood Vessels/pathology; Immunohistochemistry; Inhalation Exposure; Luminescence; Male; Mice; Mice, Knockout; Muscle Tonus/drug effects; Muscle Tonus/physiology; Muscle, Smooth, Vascular/drug effects; Muscle, Smooth, Vascular/physiology; NADPH Oxidases/biosynthesis; Particulate Matter/toxicity*; RNA/biosynthesis; RNA/genetics; Reactive Nitrogen Species/metabolism*; Reactive Oxygen Species/metabolism*; Reverse Transcriptase Polymerase Chain Reaction; Vasodilator Agents/pharmacology