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1.  Effects of urban fine particulate matter and ozone on HDL functionality 
Exposures to ambient particulate matter (PM) are associated with increased morbidity and mortality. PM2.5 (<2.5 μm) and ozone exposures have been shown to associate with carotid intima media thickness in humans. Animal studies support a causal relationship between air pollution and atherosclerosis and identified adverse PM effects on HDL functionality.
We aimed to determine whether brief exposures to PM2.5 and/or ozone could induce effects on HDL anti-oxidant and anti-inflammatory capacity in humans.
Subjects were exposed to fine concentrated ambient fine particles (CAP) with PM2.5 targeted at 150 μg/m3, ozone targeted at 240 μg/m3(120 ppb), PM2.5 plus ozone targeted at similar concentrations, and filtered air (FA) for 2 h, on 4 different occasions, at least two weeks apart, in a randomized, crossover study. Blood was obtained before exposures (baseline), 1 h after and 20 h after exposures. Plasma HDL anti-oxidant/anti-inflammatory capacity and paraoxonase activity were determined. HDL anti-oxidant/anti-inflammatory capacity was assessed by a cell-free fluorescent assay and expressed in units of a HDL oxidant index (HOI). Changes in HOI (ΔHOI) were calculated as the difference in HOI from baseline to 1 h after or 20 h after exposures.
There was a trend towards bigger ΔHOI between PM2.5 and FA 1 h after exposures (p = 0.18) but not 20 h after. This trend became significant (p <0.05) when baseline HOI was lower (<1.5 or <2.0), indicating decreased HDL anti-oxidant/anti-inflammatory capacity shortly after the exposures. There were no significant effects of ozone alone or in combination with PM2.5 on the change in HOI at both time points. The change in HOI due to PM2.5 showed a positive trend with particle mass concentration (p = 0.078) and significantly associated with the slope of systolic blood pressure during exposures (p = 0.005).
Brief exposures to concentrated PM2.5 elicited swift effects on HDL anti-oxidant/anti-inflammatory functionality, which could indicate a potential mechanism for how particulate air pollution induces harmful cardiovascular effects.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-016-0139-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4879751  PMID: 27221567
High density lipoprotein (HDL); Air pollution; HDL oxidant index (HOI); HDL function; Fine particulate matter; Cardiovascular; Ozone
2.  Heme Oxygenase-1 Protects Endothelial Cells from the Toxicity of Air Pollutant Chemicals 
Toxicology and applied pharmacology  2015;284(3):281-291.
Diesel exhaust particles (DEP) are a major component of diesel emissions, responsible for a large portion of their toxicity. In this study, we examined the toxic effects of DEP on endothelial cells and the role of DEP-induced heme oxygenase-1 (HO-1) expression. Human microvascular endothelial cells (HMEC) were treated with an organic extract of DEP from an automobile engine (A-DEP) or a forklift engine (F-DEP) for 1 and 4 hours. ROS generation, cell viability, lactate dehydrogenase leakage, expression of HO-1, inflammatory genes, cell adhesion molecules and UPR gene were assessed. HO-1 expression and/or activity were inhibited by siRNA or Tin protoporphyrin (Sn PPIX) and enhanced by an expression plasmid or Cobalt protoporphyrin (CoPPIX). Exposure to 25 μg/ml of A-DEP and F-DEP significantly induced ROS production, cellular toxicity and greater levels of inflammatory and cellular adhesion molecules but in a different degree. Inhibition of HO-1 enzymatic activity with SnPPIX and silencing of the HO-1 gene by siRNA enhanced DEP-induced ROS production, further decreased cell viability and increased expression of inflammatory and cell adhesion molecules. On the other hand, overexpression of the HO-1 gene by a pcDNA 3.1D/V5-HO-1 plasmid significantly mitigated ROS production, increased cell survival and decreased the expression of inflammatory genes. HO-1 expression protected HMEC from DEP-induced prooxidative and proinflammatory effects. Modulation of HO-1 expression could potentially serve as a therapeutic target in an attempt to inhibit the cardiovascular effects of ambient PM.
PMCID: PMC4743257  PMID: 25620054
Diesel exhaust particles; air pollution; endothelial cells; Heme oxygenase-1; reactive oxygen species; inflammation
3.  No Effect of Acute Exposure to Coarse Particulate Matter Air Pollution in a Rural Location on High Density Lipoprotein Function 
Inhalation toxicology  2014;26(1):23-29.
High density lipoprotein (HDL) particles perform numerous vascular-protective functions. Animal studies demonstrate that exposure to fine or ultrafine particulate matter (PM) can promote HDL dysfunction. However, the impact of PM on humans remains unknown.
We aimed to determine the effect of exposure to coarse concentrated ambient particles (CAP) on several metrics of HDL function.
Thirty-two adults (25.9 ± 6.6 years) were exposed to coarse CAP [76.2 ± 51.5 µg·m−3] in a rural location and filtered air (FA) for 2-hours in a randomized double-blind crossover study. Venous blood collected 2 and 20 hours post-exposures was measured for HDL-mediated efflux of [3H]-cholesterol from cells and 20 hours post-exposures for HDL anti-oxidant capacity by the HDL oxidation index (HOI) and paraoxonase activity. The changes [median (first, third quartiles)] between exposures among 29 subjects with available results were compared by matched Wilcoxon tests.
HDL-mediated cholesterol efflux capacity did not differ between exposures at either time point [16.60% (15.17, 19.19) 2-hours post-CAP versus 17.56% (13.43, 20.98) post-FA, p=0.768 and 14.90% (12.47, 19.15) 20-hours post-CAP versus 17.75% (13.22, 23.95) post-FA, p=0.216]. HOI [0.26 (0.24, 0.35) versus 0.28 (0.25, 0.40), p=0.198] and paraoxonase activity [0.54 (0.39, 0.82) versus 0.60 µmol·min−1·ml plasma−1 (0.40, 0.85), p=0.137] did not differ 20-hours post-CAP versus FA, respectively.
Brief inhalation of coarse PM from a rural location did not acutely impair several facets of HDL functionality. Whether coarse PM derived from urban sites, fine particles, or longer-term PM exposures can promote HDL dysfunction warrant future investigations.
PMCID: PMC4445365  PMID: 24417404
Air pollution; atherosclerosis; high density lipoprotein
4.  HDL anti-oxidant function associates with LDL level in young adults 
Atherosclerosis  2013;232(1):165-170.
The primary objective was to evaluate predictors of HDL anti-oxidant function in young adults.
High-density lipoprotein (HDL) cholesterol is considered a protective factor for cardiovascular disease (CVD). However, increased levels are not always associated with decreased cardiovascular risk. A better understanding of the importance of HDL functionality and how it affects CVD risk is needed.
Fifty non-Hispanic white subjects from the Testing Responses on Youth (TROY) study were randomly selected to investigate whether differences in HDL anti-oxidant function are associated with traditional cardiovascular risk factors, including carotid intima media thickness (CIMT), arterial stiffness and other inflammatory/metabolic parameters. HDL anti-oxidant capacity was evaluated by assessing its ability to inhibit low-density lipoprotein (LDL) cholesterol oxidation by air using a DCF-based fluorescent assay and expressed as a HDL oxidant index (HOI). The associations between HOI and other variables were assessed using both linear and logistic regression.
Eleven subjects (25%) had an HOI ≥ 1, indicating a pro-oxidant HDL. Age, LDL, high sensitivity C-reactive protein (hsCRP), and paraoxonase activity (PON1), but not HDL, were all associated with HOI level in univariate linear regression models. In multivariate models that mutually adjusted for these variables, LDL remained the strongest predictor of HOI (0.13 increase in HOI per 1 SD increase in LDL, 95% CI 0.04, 0.22).
Atherogenic index of plasma, pulse pressure, homocysteine, glucose, insulin, CIMT and measurements of arterial stiffness were not associated with HOI in this population.
These results suggest LDL, hsCRP and DBP might predict HDL anti-oxidant function at an early age.
PMCID: PMC4039385  PMID: 24401232
high density lipoprotein; antioxidant; paraoxonase; atherosclerosis
5.  Effect of Exposure to Atmospheric Ultrafine Particles on Production of Free Fatty Acids and Lipid Metabolites in the Mouse Small Intestine 
Background: Exposure to ambient ultrafine particulate matter (UFP) is a well-recognized risk factor for cardiovascular and respiratory diseases. However, little is known about the effects of air pollution on gastrointestinal disorders.
Objective: We sought to assess whether exposure to ambient UFP (diameter < 180 nm) increased free fatty acids and lipid metabolites in the mouse small intestine.
Methods: Ldlr-null mice were exposed to filtered air (FA) or UFP collected at an urban Los Angeles, California, site that was heavily affected by vehicular emissions; the exposure was carried out for 10 weeks in the presence or absence of D-4F, an apolipoprotein A-I mimetic peptide with antioxidant and anti-inflammation properties on a high-fat or normal chow diet.
Results: Compared with FA, exposure to UFP significantly increased intestinal hydroxyeicosatetraenoic acids (HETEs), including 15-HETE, 12-HETE, 5-HETE, as well as hydroxyoctadecadienoic acids (HODEs), including 13-HODE and 9-HODE. Arachidonic acid (AA) and prostaglandin D2 (PGD2) as well as some of the lysophosphatidic acids (LPA) in the small intestine were also increased in response to UFP exposure. Administration of D-4F significantly reduced UFP-mediated increase in HETEs, HODEs, AA, PGD2, and LPA. Although exposure to UFP further led to shortened villus length accompanied by prominent macrophage and neutrophil infiltration into the intestinal villi, administration of D-4F mitigated macrophage infiltration.
Conclusions: Exposure to UFP promotes lipid metabolism, villus shortening, and inflammatory responses in mouse small intestine, whereas administration of D-4F attenuated these effects. Our findings provide a basis to further assess the mechanisms underlying UFP-mediated lipid metabolism in the digestive system with clinical relevance to gut homeostasis and diseases.
Citation: Li R, Navab K, Hough G, Daher N, Zhang M, Mittelstein D, Lee K, Pakbin P, Saffari A, Bhetraratana M, Sulaiman D, Beebe T, Wu L, Jen N, Wine E, Tseng CH, Araujo JA, Fogelman A, Sioutas C, Navab M, Hsiai TK. 2015. Effect of exposure to atmospheric ultrafine particles on production of free fatty acids and lipid metabolites in the mouse small intestine. Environ Health Perspect 123:34–41;
PMCID: PMC4286268  PMID: 25170928
6.  Diesel exhaust particulate increases the size and complexity of lesions in atherosclerotic mice 
Diesel exhaust particulate (DEP), a major component of urban air pollution, has been linked to atherogenesis and precipitation of myocardial infarction. We hypothesized that DEP exposure would increase and destabilise atherosclerotic lesions in apolipoprotein E deficient (ApoE−/−) mice.
ApoE−/− mice were fed a ‘Western diet’ (8 weeks) to induce ‘complex’ atherosclerotic plaques, with parallel experiments in normal chow fed wild-type mice. During the last 4 weeks of feeding, mice received twice weekly instillation (oropharyngeal aspiration) of 35 μL DEP (1 mg/mL, SRM-2975) or vehicle (saline). Atherosclerotic burden was assessed by en-face staining of the thoracic aorta and histological examination of the brachiocephalic artery.
Brachiocephalic atherosclerotic plaques were larger in ApoE−/− mice treated with DEP (59±10%) than in controls (32±7%; P = 0.017). In addition, DEP-treated mice had more plaques per section of artery (2.4±0.2 vs 1.8±0.2; P = 0.048) and buried fibrous layers (1.2±0.2 vs 0.4±0.1; P = 0.028). These changes were associated with lung inflammation and increased antioxidant gene expression in the liver, but not with changes in endothelial function, plasma lipids or systemic inflammation.
Increased atherosclerosis is caused by the particulate component of diesel exhaust producing advanced plaques with a potentially more vulnerable phenotype. These results are consistent with the suggestion that removal of the particulate component would reduce the adverse cardiovascular effects of diesel exhaust.
PMCID: PMC3907045  PMID: 24330719
Diesel; Air pollution; P; Atherosclerosis; ApoE; Oxidative stress
7.  Network for Activation of Human Endothelial Cells by Oxidized Phospholipids: A Critical Role of Heme Oxygenase 1 
Circulation research  2011;109(5):e27-e41.
Ox-PAPC accumulates in atherosclerotic lesions, is pro-atherogenic, and influences the expression of over 1000 genes in endothelial cells.
To elucidate the major pathways involved in Ox-PAPC action, we conducted a systems analysis of endothelial cell gene expression after exposure to Ox-PAPC.
Methods and Results
We used the variable responses of primary endothelial cells from 149 individuals exposed to Ox-PAPC to construct a network consisting of 11 groups of genes or modules. Modules were enriched for a broad range of GO pathways, some of which have not been previously identified as major Ox-PAPC targets. Further validating our method of network construction, modules were consistent with relationships established by cell biology studies of Ox-PAPC effects on endothelial cells. This network provides novel hypotheses about molecular interactions, as well as candidate molecular regulators of inflammation and atherosclerosis. We validate several hypotheses based on network connections and genomic association. Our network analysis predicted that the hub gene CHAC1 was regulated by the ATF4 arm of the unfolded protein response pathway and here we showed that ATF4 directly activates an element in the CHAC1 promoter. We show that variation in basal levels of HMOX1 contribute to the response to Ox-PAPC, consistent with its position as a hub in our network. We also identified GPR39 as a regulator of HMOX1 levels and showed that it modulates the promoter activity of HMOX1. We further showed that OKL38/OSGN1, the hub gene in the blue module, is a key regulator of both inflammatory and anti-inflammatory molecules.
Our systems genetics approach has provided a broad view of the pathways involved in the response of endothelial cells to Ox-PAPC and also identified novel regulatory mechanisms.
PMCID: PMC3163234  PMID: 21737788
Endothelial Cells; Oxidized Phospholipids; Gene Expression; Heme Oxygenase; Network; Systems Genetics; Genome-Wide Association Studies
8.  Heme Oxygenase-1, Oxidation, Inflammation, and Atherosclerosis 
Atherosclerosis is an inflammatory process of the vascular wall characterized by the infiltration of lipids and inflammatory cells. Oxidative modifications of infiltrating low-density lipoproteins and induction of oxidative stress play a major role in lipid retention in the vascular wall, uptake by macrophages and generation of foam cells, a hallmark of this disorder. The vasculature has a plethora of protective resources against oxidation and inflammation, many of them regulated by the Nrf2 transcription factor. Heme oxygenase-1 (HO-1) is a Nrf2-regulated gene that plays a critical role in the prevention of vascular inflammation. It is the inducible isoform of HO, responsible for the oxidative cleavage of heme groups leading to the generation of biliverdin, carbon monoxide, and release of ferrous iron. HO-1 has important antioxidant, antiinflammatory, antiapoptotic, antiproliferative, and immunomodulatory effects in vascular cells, most of which play a significant role in the protection against atherogenesis. HO-1 may also be an important feature in macrophage differentiation and polarization to certain subtypes. The biological effects of HO-1 are largely attributable to its enzymatic activity, which can be conceived as a system with three arms of action, corresponding to its three enzymatic byproducts. HO-1 mediated vascular protection may be due to a combination of systemic and vascular local effects. It is usually expressed at low levels but can be highly upregulated in the presence of several proatherogenic stimuli. The HO-1 system is amenable for use in the development of new therapies, some of them currently under experimental and clinical trials. Interestingly, in contrast to the HO-1 antiatherogenic actions, the expression of its transcriptional regulator Nrf2 leads to proatherogenic effects instead. This suggests that a potential intervention on HO-1 or its byproducts may need to take into account any potential alteration in the status of Nrf2 activation. This article reviews the available evidence that supports the antiatherogenic role of HO-1 as well as the potential pathways and mechanisms mediating vascular protection.
PMCID: PMC3400084  PMID: 22833723
heme oxygenase; bilirubin; carbon monoxide; iron; oxidative stress; inflammation; atherosclerosis
9.  NF-E2–Related Factor 2 Promotes Atherosclerosis by Effects on Plasma Lipoproteins and Cholesterol Transport That Overshadow Antioxidant Protection 
To test the hypothesis that NF-E2–related factor 2 (Nrf2) expression plays an antiatherogenic role by its vascular antioxidant and anti-inflammatory properties.
Methods and Results
Nrf2 is an important transcription factor that regulates the expression of phase 2 detoxifying enzymes and antioxidant genes. Its expression in vascular cells appears to be an important factor in the protection against vascular oxidative stress and inflammation. We developed Nrf2 heterozygous (HET) and homozygous knockout (KO) mice on an apolipoprotein (apo) E–null background by sequential breeding, resulting in Nrf2−/−, apoE−/− (KO), Nrf2−/+, apoE−/− (HET) and Nrf2+/+, and apoE−/− wild-type littermates. KO mice exhibited decreased levels of antioxidant genes with evidence of increased reactive oxygen species generation compared with wild-type controls. Surprisingly, KO males exhibited 47% and 53% reductions in the degree of aortic atherosclerosis compared with HET or wild-type littermates, respectively. Decreased atherosclerosis in KO mice correlated with lower plasma total cholesterol in a sex-dependent manner. KO mice also had a decreased hepatic cholesterol content and a lower expression of lipogenic genes, suggesting that hepatic lipogenesis could be reduced. In addition, KO mice exhibited atherosclerotic plaques characterized by a lesser macrophage component and decreased foam cell formation in an in vitro lipid-loading assay. This was associated with a lower rate of cholesterol influx, mediated in part by decreased expression of the scavenger receptor CD36.
Nrf2 expression unexpectedly promotes atherosclerotic lesion formation in a sex-dependent manner, most likely by a combination of systemic metabolic and local vascular effects.
PMCID: PMC3037185  PMID: 20947826
atherosclerosis; cytokines; lipoproteins; reactive oxygen species; foam cell formation; lipogenesis; Nrf2
10.  Ambient Particulate Pollutants in the Ultrafine Range Promote Early Atherosclerosis and Systemic Oxidative Stress 
Circulation research  2008;102(5):589-596.
Air pollution is associated with significant adverse health effects, including increased cardiovascular morbidity and mortality. Exposure to particulate matter with an aerodynamic diameter of <2.5 μm (PM2.5) increases ischemic cardiovascular events and promotes atherosclerosis. Moreover, there is increasing evidence that the smallest pollutant particles pose the greatest danger because of their high content of organic chemicals and prooxidative potential. To test this hypothesis, we compared the proatherogenic effects of ambient particles of <0.18 μm (ultrafine particles) with particles of <2.5 μm in genetically susceptible (apolipoprotein E–deficient) mice. These animals were exposed to concentrated ultrafine particles, concentrated particles of <2.5 μm, or filtered air in a mobile animal facility close to a Los Angeles freeway. Ultrafine particle–exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM2.5 or filtered air. Exposure to ultrafine particles also resulted in an inhibition of the antiinflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress as evidenced by a significant increase in hepatic malondialdehyde levels and upregulation of Nrf2-regulated antioxidant genes. We conclude that ultrafine particles concentrate the proatherogenic effects of ambient PM and may constitute a significant cardiovascular risk factor.
PMCID: PMC3014059  PMID: 18202315
air pollution; ultrafine particles; atherosclerosis; oxidative stress; HDL
11.  Particulate air pollution, systemic oxidative stress, inflammation, and atherosclerosis 
Air pollution has been associated with significant adverse health effects leading to increased overall morbidity and mortality of worldwide significance. Epidemiological studies have shown that the largest portion of air pollution-related mortality is due to cardiovascular diseases, predominantly those of ischemic nature. Human studies suggest an association with atherosclerosis and increasing experimental animal data support that this association is likely to be causal. While both gasses and particles have been linked to detrimental health effects, more evidence implicates the particulate matter (PM) components as major responsible for a large portion of the proatherogenic effects. Multiple experimental approaches have revealed the ability of PM components to trigger and/or enhance free radical reactions in cells and tissues, both ex vivo as well as in vivo. It appears that exposure to PM leads to the development of systemic prooxidant and proinflammatory effects that may be of great importance in the development of atherosclerotic lesions. This article reviews the epidemiological studies, experimental animal, and cellular data that support the association of air pollutants, especially the particulate components, with systemic oxidative stress, inflammation, and atherosclerosis. It also reviews the use of transcriptomic studies to elucidate molecular pathways of importance in those systemic effects.
PMCID: PMC3040314  PMID: 21461032
Air pollution; Particulate matter; Ultrafine particles; Oxidative stress; Inflammation; Atherosclerosis; Dysfunctional HDL; Cardiovascular disease
12.  Copy number variation influences gene expression and metabolic traits in mice 
Human Molecular Genetics  2009;18(21):4118-4129.
Copy number variants (CNVs) are genomic segments which are duplicated or deleted among different individuals. CNVs have been implicated in both Mendelian and complex traits, including immune and behavioral disorders, but the study of the mechanisms by which CNVs influence gene expression and clinical phenotypes in humans is complicated by the limited access to tissues and by population heterogeneity. We now report studies of the effect of 19 CNVs on gene expression and metabolic traits in a mouse intercross between strains C57BL/6J and C3H/HeJ. We found that 83% of genes predicted to occur within CNVs were differentially expressed. The expression of most CNV genes was correlated with copy number, but we also observed evidence that gene expression was altered in genes flanking CNVs, suggesting that CNVs may contain regulatory elements for these genes. Several CNVs mapped to hotspots, genomic regions influencing expression of tens or hundreds of genes. Several metabolic traits including cholesterol, triglycerides, glucose and body weight mapped to three CNVs in the genome, in mouse chromosomes 1, 4 and 17. Predicted CNV genes, such as Itlna, Defcr-1, Trim12 and Trim34 were highly correlated with these traits. Our results suggest that CNVs have a significant impact on gene expression and that CNVs may be playing a role in the mechanisms underlying metabolic traits in mice.
PMCID: PMC2758141  PMID: 19648292
13.  Particulate matter and atherosclerosis: role of particle size, composition and oxidative stress 
Air Pollution has been associated with significant adverse health effects leading to increased morbidity and mortality. Cumulative epidemiological and experimental data have shown that exposure to air pollutants lead to increased cardiovascular ischemic events and enhanced atherosclerosis. It appears that these associations are much stronger with the air particulate matter (PM) component and that in urban areas, the smaller particles could be more pathogenic, as a result of their greater propensity to induce systemic prooxidant and proinflammatory effects. Much is still unknown about the toxicology of ambient particulates as well as the pathogenic mechanisms responsible for the induction of adverse cardiovascular health effects. It is expected that better understanding of these effects will have large implications and may lead to the formulation and implementation of new regulatory policies. Indeed, we have found that ultrafine particles (<0.18 μm) enhance early atherosclerosis, partly due to their high content in redox cycling chemicals and their ability to synergize with known proatherogenic mediators in the promotion of tissue oxidative stress. These changes take place in parallel with increased evidence of phase 2 enzymes expression, via the electrophile-sensitive transcription factor, p45-NFE2 related transcription factor 2 (Nrf2). Exposure to ultrafine particles also results in alterations of the plasma HDL anti-inflammatory function that could be indicative of systemic proatherogenic effects. This article reviews the epidemiological, clinical and experimental animal evidence that support the association of particulate matter with atherogenesis. It also discusses the possible pathogenic mechanisms involved, the physicochemical variables that may be of importance in the greater toxicity exhibited by a small particle size, interaction with genes and other proatherogenic factors as well as important elements to consider in the design of future mechanistic studies.
Extensive epidemiological evidence supports the association of air pollution with adverse health effects [1-3]. It is increasingly being recognized that such effects lead to enhanced morbidity and mortality, mostly due to exacerbation of cardiovascular diseases and predominantly those of ischemic character [4]. Indeed, in addition to the classical risk factors such as serum lipids, smoking, hypertension, aging, gender, family history, physical inactivity and diet, recent data have implicated air pollution as an important additional risk factor for atherosclerosis. This has been the subject of extensive reviews [5,6] and a consensus statement from the American Heart Association [7]. This article reviews the supporting epidemiological and animal data, possible pathogenic mechanisms and future perspectives.
PMCID: PMC2761850  PMID: 19761620
14.  Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells 
Genome Biology  2007;8(7):R149.
Gene expression analysis of human microvascular endothelial cells exposed to diesel exhaust particles and oxidized phospholipids revealed several upregulated gene modules, including genes involved in vascular inflammatory processes such as atherosclerosis.
Ambient air pollution is associated with increased cardiovascular morbidity and mortality. We have found that exposure to ambient ultrafine particulate matter, highly enriched in redox cycling organic chemicals, promotes atherosclerosis in mice. We hypothesize that these pro-oxidative chemicals could synergize with oxidized lipid components generated in low-density lipoprotein particles to enhance vascular inflammation and atherosclerosis.
We have used human microvascular endothelial cells (HMEC) to study the combined effects of a model air pollutant, diesel exhaust particles (DEP), and oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (ox-PAPC) on genome-wide gene expression. We treated the cells in triplicate wells with an organic DEP extract, ox-PAPC at various concentrations, or combinations of both for 4 hours. Gene-expression profiling showed that both the DEP extract and ox-PAPC co-regulated a large number of genes. Using network analysis to identify coexpressed gene modules, we found three modules that were most highly enriched in genes that were differentially regulated by the stimuli. These modules were also enriched in synergistically co-regulated genes and pathways relevant to vascular inflammation. We validated this synergy in vivo by demonstrating that hypercholesterolemic mice exposed to ambient ultrafine particles exhibited significant upregulation of the module genes in the liver.
Diesel exhaust particles and oxidized phospholipids synergistically affect the expression profile of several gene modules that correspond to pathways relevant to vascular inflammatory processes such as atherosclerosis.
PMCID: PMC2323217  PMID: 17655762
15.  Cigarette smoking is associated with dose-dependent adverse effects on paraoxonase activity and fibrinogen in young women 
Inhalation Toxicology  2014;26(14):861-865.
Smoking is associated with increased fibrinogen and decreased paraoxonase (PON) activity, markers of inflammation and oxidative stress, in patients with coronary artery disease.
We tested the hypothesis that the adverse effect of smoking on these biomarkers of inflammation and oxidative stress would be detectable in otherwise healthy young female habitual smokers.
Materials and methods
Thirty-eight young women participated in the study (n = 20 habitual smokers, n = 18 non-smokers). Fibrinogen, PON-1 activity and HDL oxidant index (HOI) were measured.
Mean values of fibrinogen, PON-1 activity and log HOI were not different between the groups. Importantly, however, decreased PON-1 activity (r s = −0.51, p = 0.03) and increased fibrinogen (rs = 0.49, p = 0.04) were significantly correlated with increasing number of cigarettes smoked per day in habitual smokers.
Discussion and conclusion
Cigarette smoking is associated with a dose-dependent adverse effect on PON-1 activity and fibrinogen in young women, which may have implications for future cardiovascular risk.
PMCID: PMC4266070  PMID: 25472476
Fibrinogen; paraoxonase activity; smoking; women

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