2009 Progress Report: Atherothrombotic Effects of Particulate Matter

EPA Grant Number: EM833367
Title: Atherothrombotic Effects of Particulate Matter
Investigators: Bhatnagar, Aruni , Conklin, Daniel
Institution: University of Louisville
EPA Project Officer: Chung, Serena
Project Period: August 1, 2007 through July 31, 2010
Project Period Covered by this Report: August 1, 2008 through July 31,2009
Project Amount: $1,500,000
RFA: Targeted Research Grant (2007) Recipients Lists
Research Category: Targeted Research , Particulate Matter


To understand the atherothrombotic effects of concentrated ambient fine particulate matter (CAPs, PM2.5) exposure in mice

Progress Summary:

In summer 2009, we began performing CAPs exposures with mice and initiated studies to characterize the concentration and performance efficiency of VACES throughout the year. Results from these studies are summarized below.

A. Louisville PM Studies

  1. Louisville PM2.5 Elemental Composition:
    Filter samples from pre-VACES and post-VACES sites were collected over several days, mass was measured, and filters were then shipped to Dr. L.C. Chen (NYU) for elemental analysis by X-ray flame ionization detection (XRFID). Ambient PM2.5 elemental content was calculated from raw data according to standard methods and data are summarized in Table 1. Ambient Louisville air was drawn through a Cyclone collector (~100 lpm) to separate PM2.5 from larger PM fraction and then a controlled flow (~10 lpm) was collected on a Teflon filter (0.2 µm; Pall) for elemental and mass analyses (Fig. 1A-C). Similarly, a separate flow of VACES-concentrated air (post-diffusion drying; ~1 lpm) was filter collected for mass and elemental analyses. Elemental analysis indicated that the VACES system was both maintaining ambient PM2.5 composition (e.g., the top 15 elements by abundance are present in both pre- and post-VACES analyses; Chart 1AB) and was on average concentrating ambient PM2.5 between 8 and 10 times ambient level (see Ratio in Table 1). This elemental analysis agrees well in both level of elements in PM2.5 fraction for ambient urban air but also appears similar in profile to the PM2.5 in air in Steubenville, OH (of “Six Cities Study” fame), which is also in the Ohio River Valley ~300 miles east of Louisville (for comparison see Laden et al., 2000) 5. Interestingly, a feature of Louisville PM2.5 shared in common with Steubenville PM2.5 is a relatively high iron content (Table 1; Chart 1).
  2. Louisville PM2.5 Concentration Efficiency:
    To establish that UofL VACES is effectively concentrating PM2.5 from the larger ambient PM fraction, we assessed the mass concentration by filtering air at both pre- and post-VACES sites. Teflon filters were temperature and humidity equilibrated for pre- and post-exposure weighing on a microbalance. Results of a multiday collection of PM on filters indicated visibly more particulate on ambient (pre-VACES) and post-VACES filters, whereas HEPA-filtered air served as a control (Fig. 1C). Filter mass was correspondingly and similarly increased in ambient and VACES filters. Because filter mass was similar but air flow was 10x greater for ambient than for post-VACES collection, the calculated ratio (or concentration efficiency) was ~10x (Fig. 1D). These data were supported by real-time monitoring of post-VACES air with the DataRAM4, which indicated an appropriate particle size distribution (Fig. 1E) and an ~16-times concentration efficiency when compared with hourly EPA monitoring data of ambient PM2.5 in west Louisville air near “Rubbertown” (Fig. 1F; see Southwick site).
  3. Louisville PM2.5 Particle Size Distribution:
    Through spring and summer of 2009 we have operated the VACES and documented PM2.5 mass concentration and median particle size distribution using in line DataRAM4 (ThermoElectron; Fig. 2). These data have been compared with monitoring site data provided by Louisville Metro Air Pollution Control District (APCD; http://www.louisvilleky.gov/APCD/ambient/AmbientSites.htm) to better appreciate the overall function of our VACES under ambient conditions (Fig. 3). Thus, preliminary findings indicate that PM2.5 mass concentration collected by the VACES fluctuates on a day-to-day basis similarly to PM2.5 in the greater Louisville area (Fig. 3C, bottom panel). As it is, the UofL VACES is housed on the 7th floor of the Medical-Dental Research Building in downtown Louisville within ~½ mile of Interstate I-65 (see Louisville map). We have collected PM2.5 data on the rooftop and at street level of this building for further comparison (Fig. 4). There was strong correspondence between real-time mass concentration and median particle diameter measurements performed on the rooftop and at street level (Fig. 4), and this further supports that the 7th floor site of the inhalation facility is an excellent collection site for Louisville air PM2.5.
  4. Results of Acute PM2.5 Exposures in Mice:
    1. Effects on Plasma Lipids.
      Mice (C57Bl/6, male, 12-weeks old; Jackson Laboratory, Bar Harbor, ME) were fed either normal rodent chow (NC; 13.5% kcal fat) or a high-fat diet (HFD; 60% kcal fat, lard) for 6 weeks before onset of exposure. Plasma total, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol along with several other plasma components were measured with an automated Cobas-Mira (Roche) after 9 consecutive days of concentrated ambient PM2.5 (PM) or HEPA-filtered (HEPA) air exposure (6h/d). Mice were fasted 16h before euthanization. PM exposure, independent of diet, significantly increased total and HDL cholesterol but not LDL cholesterol (Fig. 5). No other measured factor, including body weight, organ/body weight ratios (heart, liver, lung, spleen), triglycerides, non-esterified fatty acids, albumin, total protein, ALT, AST, creatine kinase, creatinine, and HbA1c, was affected by PM independent of diet. However, HFD-fed mice had significantly higher plasma albumin and total protein levels and lower organ/body weight ratios (heart, liver, lung, spleen) than matched HFD-fed HEPA-exposed controls, indicating that HFD made these mice more susceptible to PM-induced toxicity. In a separate study, normal chow-fed C57Bl/6 mice were exposed to HEPA-filtered air or CAPS for 3 consecutive days, then unexposed for 4 days, followed by exposure for another 4 days. These mice had no changes in any lipids, including cholesterol (HEPA-air: 70.7±0.4; PM-exposed: 72.4±2.1 mg/dL, n=4,4, respectively), indicating that extended PM exposure, not intermittent exposure, is likely necessary for PM-induced dyslipidemia. Although PM induced an increase in HDL cholesterol, we do not assume this is necessarily an indication that this is an atheroprotective HDL phenotype. On the contrary, accumulation of nascent HDL will occur as a product of decreased reverse cholesterol clearance, and thus, HDL function will be measured in future PM exposures whether HDL is increased by PM exposure or not to ascertain the functional significance of this change.
    2. Effects on Endothelial Dysfunction, Insulin Resistance, and Circulating EPCs.
      To assess vascular function following PM exposure, the aorta was isolated and vascular reactivity ex vivo with phenylephrine (PE), acetycholine (ACh) and sodium nitroprusside (SNP) was measured as previously published 6 . There was no significant change in aortic contractility with PE or in endothelial-dependent (ACh) or –independent (SNP) relaxation in NC- or HFD-fed PM-exposed mice compared with HEPA-air-exposed and diet-matched control mice (data not shown). However, group sizes were only 4 mice per group in this initial experiment, and therefore, this experiment will be repeated in the near future to increase group size. Despite no change in endothelial function (often used as a sign of vascular injury of PM exposure; see Campen, 2009; Nurkiewicz et al., 2009) 7, 8 , the biochemical responses of isolated aorta and perfused heart ex vivo to insulin have revealed a PM-dependent insulin resistance in these tissues. Because previous studies of PM exposure showed that this phenomenon occurs after chronic PM exposure 4 , these new results indicate insulin resistance in the cardiovascular tissues could occur much earlier than in other peripheral tissues (data not shown). Therefore, insulin resistance (and a potential mechanism of ER stress and the unfolded protein response, UPR) will add a new line of inquiry to the ongoing PM studies and this direction will dovetail nicely with our new Diabetes and Obesity Center at UofL (Bhatnagar, Director), which will provide a variety of resources for such studies. Additionally, the level of circulating EPCs also was measured in these same studies because this parameter appears to be a more sensitive marker of cardiovascular injury and disease risk in both humans and animal models than is strict measurement of aortic reactivity. Thus, we have expanded our capacity to measure a variety of important physiological endpoints in order to best detect subtle effects of PM exposure that reveal the potential mechanistic information of PM action.

      In contrast to the lack of a PM-dependent effect on aortic endothelial function, mice exposed for nine consecutive days to Louisville CAPS had significantly fewer circulating EPCs (Flk-1+/Sca-1+) than did matched HEPA-air exposed controls (Fig. 6A & B). After exposure, mice were euthanized and the mononuclear cells (MNCs) in peripheral blood were isolated. These cells were then stained with antibodies against Flk-1 (VEGF receptor, R2) and Sca-1 (stem cell marker) and analyzed by FACS. These data indicate that EPCs are a more subtle marker of cardiovascular response to PM exposure than is endothelial function ex vivo. In future studies, we will further examine the time course of PM-dependent effects and determine whether increased cholesterol was also related to changes in circulating EPC numbers.

    3. Comparison with Acrolein Inhalation Studies.
      Because our basic premise states that environmental aldehydes contribute to the cardiovascular toxicity of air, water, and food pollutants – and especially as a component of fine and ultrafine PM - we have performed dose- and time-dependent acrolein inhalation exposures in mice. Collectively, data from these studies indicate that acrolein induces prothrombotic and proatherosclerotic changes in a dose-dependent manner, and these results are being readied for publication. Additionally, in recent experiments, the number and function of bone marrow and circulating EPCs were measured following four-day acrolein exposure (1 ppm) using flow cytometry. Similar to the effects of nine-day PM exposure, acrolein significantly depressed circulating EPC level in mice (Fig. 7). Because of these new findings, we are developing new approaches to investigate effects of environmental exposures on EPCs as well as leukocytes (monocytes) and platelets. These findings are being assembled for publication.

B. Collaborative PM Studies:

Exposure to elevated concentrations of ambient particulate matter (PM) air pollution has been implicated as a risk factor for cardiovascular disease and mortality 9-11. Long-term repeated exposure to PM has been linked to ischemic heart disease, and empirical patterns of PM mortality associations are consistent with the hypothesis that PM exposure contributes to pulmonary and systemic oxidative stress, inflammation, atherosclerosis, and increased risk of ischemic heart disease and death 12. Long-term PM exposure has been associated with sub-clinical chronic inflammatory lung injury and sub-clinical atherosclerosis 13, 14. In heritable hyperlipidemic rabbits, PM exposure accelerated progression of atherosclerotic plaques and increased vulnerability to plaque rupture PM-potentiated vascular inflammation, and atherosclerosis were also observed in a study of apoE-null (hyperlipidemic) mice exposed to environmentally relevant concentrations of fine PM 15.

Short-term PM exposures may also play a role in triggering acute ischemic heart disease events. Short-term elevated PM exposures and related inflammation may contribute to acute complications of atherosclerosis by increasing the risk of atherosclerotic plaque rupture, thrombosis, and precipitation of acute ischemic events. Evidence that short-term exposure to PM air pollution can trigger myocardial infarction (MI) has been observed in several general population studies.

Increased short-term PM exposure has also been associated with ischemic stroke, electrocardiographic ST-segment depression, increased plasma viscosity, and increased circulating markers of inflammation 16, 17 . Based on case-crossover studies of patients who lived on Utah’s Wasatch Front, PM exposures for 1 to a few days contributed to acute ischemic coronary events, especially among patients with underlying coronary artery disease, and exposure for approximately 2 weeks contributed to increased risk of heart failure hospitalization 18.

Progenitor cell mobilization and homing can also be impacted by exogenous factors including advanced age, disease, and an unhealthy lifestyle 3, 19, 20. Indeed, impaired progenitor cell mobilization under these conditions may contribute to cardiovascular disease (CVD) risk 21-23. Thus, an understanding of mechanisms regulating progenitor mobilization and homing might suggest novel interventions to assist wound healing and to treat hypertension, atherosclerosis, retinopathy, and kidney disease. Recent studies on EPCs identify a correlation between many important cardiovascular disease risk factors and EPC activity. For example, short-term exposure to secondhand smoke exposure depresses EPC activity and decreases their ability to form new blood vessels 24 and it has been shown that smoking significantly impedes the healing of a variety of acute surgical wounds 25. These studies provide a strong rationale for studying changes in EPC and wound healing upon exposure to environmental pollutants and air toxics.

We have developed methods for studying human blood EPCs (Fig. 8), and we have initiated a human study with Dr. C.A. Pope (BYU). We have received samples (n=16 subjects) from Dr. Pope (BYU) at various times (n=4 sample times) during a PM inversion event (Fig. 9) in winter 2009, and the EPCs in blood were measured at UofL as indicated by FACS (Fig. 10). Because EPC number was significantly and inversely correlated with PM level, these data indicate that human EPCs were responsive to the effects of PM exposure in healthy adults (Fig. 10). Additionally, four other parameters were positively correlated with PM, including the number of platelet-monocyte interactions (a prothrombotic measurement), total plasma protein concentration, total plasma globulin protein concentration, and HDL cholesterol level (data not shown; these data are currently being readied for publication). Interestingly, some of these same changes (e.g., EPCs level and HDL cholesterol were observed in mice exposed to subchronic PM at the UofL. These results appear to reveal sensitive markers of cardiovascular response, perhaps acute injury, with acute exposures to relatively high levels of PM in healthy humans and animals. Thus, each specific change provides an important and compelling rationale for subsequent mechanistic studies, which are being pursued.


Text Box:
(A) Photographs of VACES inlet (left) and system (right) showing 4 lines that carry ambient air either to HEPA-filtered chambers or for concentration of PM2.5.  (B) Schematic of VACES identifying major components in serial arrangement for delivery of HEPA-filtered air, PM2.5 to one of 4 animal chambers (C1-C4). (C) Photograph of Teflon filters from HEPA-filtered air, post-Cyclone concentrator air (ambient PM2.5 fraction), and post-chamber PM2.5 (concentrated ambient PM2.5 fraction; note: 1/10th air flow of post-Cyclone). (D) Filter mass and estimated particle concentration after 12-day VACES operation and filter collection. Particle concentration (µg/m3) calculation was mass divided by filter air flow, and was >10x concentrated by the UofL VACES. (E) Plots showing the logarithm of the particle diameter as a function of the fraction cumulative mass less than or equal to the corresponding y-axis diameter (e.g., an average of 90 percent of the particles sampled were less than or equal to 1 μm diam.). (F) Scatterplot of instantaneous PM2.5 mass concentrated by the UofL VACES vs. corresponding PM2.5 levels of ambient air sampled hourly at an EPA air monitoring Southwick site in metropolitan Louisville.
Figure 1: University of Louisville versatile aerosol enrichment concentration system (VACES).

Text Box:
Louisville PM2.5 concentrated by UofL Inhalation Facility VACES.  (a) Time series plot of enriched airborne PM2.5 mass concentration from June to August 2009. Two-dimensional distribution of enriched PM2.5 mass concentration (y-axis) vs. corresponding values for particle diameter (x-axis) shown in scatterplot (b) and bivariate histogram (c) configurations (legend denotes colors corresponding to relative frequency values along the z-axis; r2 = 0.199). (d) Univariate particle size distribution for the set of instantaneous data collected during the experimental period (n=54,707).
Figure 2: Particle size distribution of ambient Louisville air by University of Louisville versatile aerosol enrichment concentrator system (VACES).

Text Box:
Figure 3: Louisville air monitoring sites and PM2.5 comparison with UofL VACES.

Text Box: EPA (AQS) Site #	Site Name	Pollutants
21-111-0027	Bates	O3, PM2.5
21-111-0043	Southwick	PM10, PM2.5
21-111-0044	Wyandotte	PM10, PM2.5
21-111-0051	Watson Lane	O3, SO2, PM2.5
21-111-0067	Cannons Lane	PM2.5
21-111-1019	Fire 20	CO
21-111-1021	WLKY TV	O3, NOx
21-111-1041	Firearms Training	SO2
Text Box:

Note: Lower panel depicts overlay of UofL VACES PM2.5 data (DataRAM4; mean) on Louisville Metro Air Pollution Control District data from 3 different sites over 12 days (August 2009).

Figure 4: Louisville ambient air PM2.5 data from rooftop and street level of the UofL Inhalation Facility.

Text Box:  Text Box:
Left panel: Street level PM2.5 mass concentration (blue) and median particle size (pink). Note: Spike fluctuation in street level PM2.5 was due to the presence of a street sweeper.
Right panel: Rooftop PM2.5 mass concentration (blue) and median particle size (pink) monitored for 1h near midday (DataRAM4). There was a strong agreement between levels measured on the rooftop and those measured at street level.

Text Box:
Figure 5: Effects of subchronic PM2.5 inhalation on murine plasma cholesterol.
Plasma total (left), high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol were measured with an automated Cobas-Mira (Roche) after 9 consecutive days of concentrated ambient PM2.5(PM) or HEPA-filtered (HEPA) air exposure. Mice (C57Bl/6, male, 12-weeks old) were fed either normal rodent chow (NC; 13.5% kcal fat) or a high-fat diet (60 % kcal fat, lard) for 6 weeks before exposure. Mice were fasted 16h before euthanization. *, p<0.05 vs. matched HEPA air-exposed control.

Text Box:
Figure 6: Effect of subchronic PM2.5 inhalation on murine circulating endothelial progenitor cells (EPCs).
Mice exposed to CAPS (PM) had a reduced number of EPCs compared with mice exposed to filtered air. (A) Group data, and (B) FACS plots, where SSC = side scatter and FSC = forward scatter. *, p<0.05.

Text Box:
Figure 7: Effect of subchronic acrolein inhalation on murine circulating endothelial progenitor cells (EPCs).
Mice were exposed to either filtered air (control) or acrolein (treated) and circulating EPC levels were quantified by flow cytometry. (A) Group data; (B) FACS plots. Cells in quadrant P3 that were dual positive for Flk-1 and Sca-1 were quantified as EPCs (#/µl blood). *, p<0.05 vs. air-matched group.

Text Box: Figure 8: Flow cytometric analysis of human EPCs. Lymphocyte populations selected from a FSC vs. SSC dot blot (panel A) will be analyzed for the presence of red blood cells, platelets and dead cells by Pacific Blue staining (panel B). A negative population from this analysis will then be further analyzed for the presence of monocytes/granulocytes by staining with antibodies against CD14 and CD16 (panel C). Finally, a negative population from this analysis will be selected and analyzed for defined EPC markers (ex. CD45, CD31) as illustrated in panel D.

Figure 9: Ambient PM2.5 level during winter inversion in and around Provo, Utah, in 2009. Blood draws were done 4 times in each of 2 sets of 8 healthy young adult humans (red spot) before, during, and after peak PM2.5 level. Blood was processed, separated, and shipped to the University of Louisville for analyses of blood/plasma factors.

Figure 10: Significant inverse relationship between human circulating endothelial progenitor cell (EPC) number and PM2.5 level. Blood was drawn from 16 healthy young adults at 4 different time points during a winter inversion in Utah, and levels of EPCs were measured at the University of Louisville by FACS.

Table 1. Elemental composition of Louisville downtown air PM2.5 fraction.

Air samples were filter collected pre- and post-versatile aerosol concentration enhancement system (VACES) and composition measured by X-ray flame ionization detection (XRFID). All other elements analyzed were below the limit of detection (ng/cm2). Ambient represents filter data from post-Cyclone but pre-VACES collection site; VACES = filter collection of post-VACES concentrated PM2.5; Ratio value = VACES value ÷ Ambient value (~measure of concentration efficiency factor of VACES for single element).

Chart 1: Pie charts showing elemental composition of downtown Louisville air PM2.5 fraction. Text Box:
Text Box:
A) Ambient PM2.5 elemental composition pre-VACES.         B) Ambient PM2.5 elemental composition post-VACES.

Future Activities:

We plan to carry out animal exposure experiments as planned. The facility and VACES construction is now complete, and we are moving swiftly to the next phase of the project. This phase is to perform acute and chronic exposures in mice (CAPs). In addition, we will use genetically-engineered mice to interrogate the role of specific particulate matter constituents (e.g., metals, aldehydes) by comparing the biological responses elicited by CAP exposures in the different mice models.





1.            Ng SP, Conklin DJ, Bhatnagar A, Bolanowski DD, Lyon J, Zelikoff JT. Prenatal exposure to cigarette smoke induces diet- and sex-dependent dyslipidemia and weight gain in adult murine offspring. Environ Health Perspect. 2009;117(7):1042-1048.

2.            Campen MJ, Lund AK, Knuckles TL, Conklin DJ, Bishop B, Young D, Seilkop S, Seagrave J, Reed MD, McDonald JD. Inhaled diesel emissions alter atherosclerotic plaque composition in ApoE(-/-) mice. Toxicol Appl Pharmacol. 2009.

3.            Werner N, Nickenig G. Influence of cardiovascular risk factors on endothelial progenitor cells: limitations for therapy? Arterioscler.Thromb.Vasc.Biol. 2006;26(2):257-266.

4.            Sun Q, Yue P, Deiuliis JA, Lumeng CN, Kampfrath T, Mikolaj MB, Cai Y, Ostrowski MC, Lu B, Parthasarathy S, Brook RD, Moffatt-Bruce SD, Chen LC, Rajagopalan S. Ambient air pollution exaggerates adipose inflammation and insulin resistance in a mouse model of diet-induced obesity. Circulation. 2009;119(4):538-546.

5.            Laden F, Neas LM, Dockery DW, Schwartz J. Association of fine particulate matter from different sources with daily mortality in six U.S. cities. Environ.Health Perspect. 2000;108(10):941-947.

6.            Conklin DJ, Haberzettl P, Prough RA, Bhatnagar A. Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke. Am.J.Physiol Heart Circ.Physiol. 2009;296(5):H1586-H1597.

7.            Campen MJ. Nitric oxide synthase: "enzyme zero" in air pollution-induced vascular toxicity. Toxicol Sci. 2009;110(1):1-3.

8.            Nurkiewicz TR, Porter DW, Hubbs AF, Stone S, Chen BT, Frazer DG, Boegehold MA, Castranova V. Pulmonary nanoparticle exposure disrupts systemic microvascular nitric oxide signaling. Toxicol Sci. 2009;110(1):191-203.

9.            Brook RD, Franklin B, Cascio W, Hong Y, Howard G, Lipsett M, Luepker R, Mittleman M, Samet J, Smith SC, Jr., Tager I. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation. 2004;109(21):2655-2671.

10.          Dockery DW, Pope CA, III, Xu X, Spengler JD, Ware JH, Fay ME, Ferris BG, Jr., Speizer FE. An association between air pollution and mortality in six U.S. cities. N.Engl.J.Med. 1993;329(24):1753-1759.

11.          Pope CA, III, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation. 2004;109(1):71-77.

12.          Pope CA, III. Mortality effects of longer term exposures to fine particulate air pollution: review of recent epidemiological evidence. Inhal.Toxicol. 2007;19 Suppl 1:33-38.

13.          Pope CA, III, Dockery DW. Health effects of fine particulate air pollution: lines that connect. J.Air Waste Manag.Assoc. 2006;56(6):709-742.

14.          Pope CA, III, Hansen ML, Long RW, Nielsen KR, Eatough NL, Wilson WE, Eatough DJ. Ambient particulate air pollution, heart rate variability, and blood markers of inflammation in a panel of elderly subjects. Environ.Health Perspect. 2004;112(3):339-345.

15.          Sun Q, Wang A, Jin X, Natanzon A, Duquaine D, Brook RD, Aguinaldo JG, Fayad ZA, Fuster V, Lippmann M, Chen LC, Rajagopalan S. Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model. JAMA. 2005;294(23):3003-3010.

16.          Pope CA, III, Muhlestein JB, May HT, Renlund DG, Anderson JL, Horne BD. Ischemic heart disease events triggered by short-term exposure to fine particulate air pollution. Circulation. 2006;114(23):2443-2448.

17.          Peters A, Frohlich M, Doring A, Immervoll T, Wichmann HE, Hutchinson WL, Pepys MB, Koenig W. Particulate air pollution is associated with an acute phase response in men; results from the MONICA-Augsburg Study. Eur.Heart J. 2001;22(14):1198-1204.

18.          Pope CA, 3rd, Renlund DG, Kfoury AG, May HT, Horne BD. Relation of heart failure hospitalization to exposure to fine particulate air pollution. Am J Cardiol. 2008;102(9):1230-1234.

19.          Chang EI, Loh SA, Ceradini DJ, Lin SE, Bastidas N, Aarabi S, Chan DA, Freedman ML, Giaccia AJ, Gurtner GC. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation.116(24):2818-29. 2007.

20.          Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ.Res. 2001;89(1):E1-E7.

21.          Goldschmidt-Clermont PJ. Loss of bone marrow-derived vascular progenitor cells leads to inflammation and atherosclerosis. [Review] [34 refs]. American Heart Journal.146(4 Suppl):S5-12. 2003.

22.          Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N.Engl.J.Med. 2003;348(7):593-600.

23.          Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, Pippen AM, Annex BH, Dong C, Taylor DA. Aging, progenitor cell exhaustion, and atherosclerosis.[see comment]. Circulation.108(4):457-63. 2003.

24.          Heiss C, Amabile N, Lee AC, Real WM, Schick SF, Lao D, Wong ML, Jahn S, Angeli FS, Minasi P, Springer ML, Hammond SK, Glantz SA, Grossman W, Balmes JR, Yeghiazarians Y. Brief secondhand smoke exposure depresses endothelial progenitor cells activity and endothelial function: sustained vascular injury and blunted nitric oxide production. J.Am.Coll.Cardiol. 2008;51(18):1760-1771.

25.          Whiteford L. Nicotine, CO and HCN: the detrimental effects of smoking on wound healing. [Review] [31 refs]. British Journal of Community Nursing.8(12):S22-6. 2003.







Journal Articles on this Report : 6 Displayed | Download in RIS Format

Other project views: All 25 publications 18 publications in selected types All 16 journal articles
Type Citation Project Document Sources
Journal Article Campen MJ, Lund AK, Knuckles TL, Conklin DJ, Bishop B, Young D, Sielkop SK, Seagrave JC, Reed MD, McDonald JD. Inhaled diesel emissions alter atherosclerotic plaque composition in ApoE-/- mice. Toxicology and Applied Pharmacology 2010;242(3):310-317. EM833367 (2009)
EM833367 (Final)
  • Abstract from PubMed
  • Full-text: Science Direct
  • Other: Science Direct PDF
  • Journal Article Conklin DJ, Haberzettl P, Prough RA, Bhatnagar A. Glutathione S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke. American Journal of Physiology Heart and Circulatory Physiology 2009;296(5):H1586-H1597. EM833367 (2008)
    EM833367 (2009)
    EM833367 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Full-text: AJP-Heart
  • Abstract: AJP-Heart
  • Other: AJP-Heart PDF
  • Journal Article Haberzettl P, Vladykovskaya E, Srivastava S, Bhatnagar A. Role of endoplasmic reticulum stress in acrolein-induced endothelial activation. Toxicology and Applied Pharmacology 2009;234(1):14-24. EM833367 (2008)
    EM833367 (2009)
    EM833367 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Science Direct HTML
  • Abstract: Science Direct
  • Other: Science Direct PDF
  • Journal Article Ng SP, Conklin DJ, Bhatnagar A, Bolanowski DD, Lyon J, Zelikoff JT. Prenatal exposure to cigarette smoke induces diet- and sex-dependent dyslipidemia and weight gain in adult murine offspring. Environmental Health Perspectives 2009;117(7):1042-1048. EM833367 (2009)
    EM833367 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: EHP
  • Abstract: EHP
  • Journal Article O'Toole TE, Zheng YT, Hellmann J, Conklin DJ, Barski O, Bhatnagar A. Acrolein activates matrix metalloproteinases by increasing reactive oxygen species in macrophages. Toxicology and Applied Pharmacology 2009;236(2):194-201. EM833367 (2008)
    EM833367 (2009)
    EM833367 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Science Direct-Full Text HTML
  • Abstract: Science Direct
  • Other: Science Direct-Full Text PDF
  • Journal Article O’Toole TE, Conklin DJ, Bhatnagar A. Environmental risk factors for heart disease. Reviews on Environmental Health 2008;23(3):167-202. EM833367 (2009)
    EM833367 (Final)
    R834514 (2011)
    R834514 (Final)
  • Abstract from PubMed
  • Abstract: ResearchGate-Abstract
  • Supplemental Keywords:

    acrolein, aldehydes, antioxidant response, endothelial progenitor cells (EPCs), endothelial dysfunction, fine PM (PM2.5), insulin resistance, metals, thrombosis, ultrafine PM (UFP);

    Progress and Final Reports:

    Original Abstract
  • 2008 Progress Report
  • Final Report