Ambient Particulates Alter Vascular Function through Induction of Reactive Oxygen and Nitrogen Species

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.

Formation of chlorinated lipids post-chlorine gas exposure

“…For example, animals exposed to Cl 2 and returned to room air develop endothelial and myocardial dysfunction and failure (13,16). This pattern of injury is observed with many chemically distinct inhaled irritants and pollutants (e.g., ozone, particulate matter) (39)(40)(41)(42). A key question is how exaggerated methacholine effects; however, 2-Cl-Pald had no effect.…”

Air Pollution, Lipids and Atherosclerosis

“…Six studies have been reported where concentrated PM 2.5 led to enhanced atherosclerosis in apolipoprotein E null mice (Apo E -/-). For example, animals were exposed to fi ne CAPs in both suburban Sterling Forest, New York (Chen and Nadziejko 2005 ;Chen et al 2010 ;Sun et al 2005Sun et al , 2008Quan et al 2010 ) or in urban Manhattan, New York (Ying et al 2009 ) and the CAPs from both environments had accelerating effects on atherosclerosis. Chen and Nadziejko fi rst reported that 39-41 week-old ApoE -/-mice fed a chow diet and exposed to 10X ambient concentrations of PM 2.5 for 6 h per day, 5 days per week for 5 months led to a 57 % increase in the percentage of atherosclerotic plaque area in the aortic root (Gunnison and Chen 2005 ) (Table 9.2 ).…”

“…Concentrated PM 2.5 appears to exert a greater promotion of plaque formation when compared to inhaled side-stream tobacco smoke and assessed by ultrasound bio-microscopy . Of interest, while the majority of studies with PM 2.5 exposures have reported increased atherosclerotic burden (Chen and Nadziejko 2005 ;Sun et al 2005Sun et al , 2008Quan et al 2010 ;Ying et al 2009 ), comparable studies of the effects of inhalation of diesel exhaust report only changes in plaque composition (Campen et al 2010 ;Bai et al 2011 ). Only a single study to date has reported that a 5-month exposure to whole diesel exhaust leads to enhanced size of atherosclerotic plaques in the brachiochephalic artery .…”

“…For example, while 4-6 month-exposures to concentrated PM 2.5 in New York (Chen and Nadziejko 2005 ;Chen et al 2010 ;Sun et al 2005Sun et al , 2008Ying et al 2009 ) yielded positive results, 5-week exposures to concentrated PM 2.5 in Los Angeles only resulted in a non-statistically signifi cant trend for increased atherosclerotic lesions (Araujo et al 2008 ). Further, while the study from Ying et al showed that 4-month inhalation exposures to concentrated PM 2.5 from the Upper East side of Manhattan (6 h/day, 5 days/week) of cholesterol enriched diet (CED)-fed 6-week-old ApoE -/-mice resulted in ~89 % increase in aortic atherosclerotic plaques over controls (Ying et al 2009 ), CED-fed mice that were exposed for 5-6 months to CAPs from Sterling Forest, New York resulted in a 58-68 % increase in atherosclerotic lesions over controls (Sun et al 2005(Sun et al , 2008. As noted by the authors, the larger effects with the Manhattan PM 2.5 could have been due to higher PM 2.5 levels and/or a higher relative content of organic carbon (OC) and elemental carbon (EC) in the Manhattan PM 2.5 (Ying et al 2009 ).…”

Update in Environmental and Occupational Medicine 2009

“…As filtration of the PM did not significantly alter these vascular responses, they concluded that the gaseous portion of the exhaust was a principal driver (35). In a concentrated ambient particle exposure study using ApoE 2/2 mice, Ying and colleagues found that ambient PM enhances atherosclerosis through the NAD(P)H oxidase-dependent induction of vascular reactive oxygen species (ROS) and reactive nitrogen species, causing decreased guanine cyclase-dependent arterial constriction in response to phenylephrine (36). The same group of investigators reported that PM 2.5 causes activation of the Rho-Rho kinase pathway in aorta and myocardium, promoting cardiac fibrosis in mice (37).…”