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Chronic exposure to ambient particulate matter alters cardiac gene expression patterns and markers of oxidative stress in rats

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Abstract

Exposure to ambient particulate matter (PM) significantly increases cardiovascular morbidity and mortality in the general population. We hypothesized that some components of PM can affect the gene expression patterns in the hearts of rats exposed for 3 months to filtered air (FA), coarse (CP; 2.5 < dp < 10 μm), fine (FP; dp ≤ 2.5 μm) or ultrafine (UFP; dp ≤ 0.18 μm) components of PM. The median diameters of CP, FP, and UFP were 3 μm, 0.7 μm and 0.07 μm, respectively. Exposures (n = 8 per group) were performed using a particle concentrator system in Riverside, California, an area with high ambient levels of photochemically derived gaseous and particulate pollutants. At the end of the exposure, hearts were subjected to gene expression profiling by using Illumina RatRef-12 bead chips and levels of malonaldehyde (MDA), a biomarker of oxidative stress, were measured. Applying fold ratio >1.5 (for both up- and down-regulated genes), we found three genes in the CP and nine genes in the UFP groups with significantly changed expression, compared with FA. No significant changes in gene expression patterns were observed in the FP group. In the UFP group thioredoxin interacting protein (Txnip), a negative regulator of an antioxidant enzyme thioredoxin, and cytochrome P450 (Cyp2e1), an enzyme involved in the metabolism of foreign substances demonstrated significant up-regulation (fold ratios 1.79 and 1.57, respectively, with false discovery rate, FDR < 0.05). In the CP group there was also a trend towards increased Txnip expression (fold ratio 1.43, FDR > 0.05) and significant increase in the Cyp2e1 expression (fold ratio 1.79, FDR < 0.05). Changes in the Txnip and Cyp2e1 expression showed statistically significant positive correlation to each other (p < 0.0009) and were confirmed by real-time PCR. In addition Txnip and Cyp2e1 expression demonstrated statistically significant moderate correlation with the levels of MDA in the heart. Up-regulation of both Cyp2e1 and Txnip are observed in hearts of patients with certain cardiac diseases. Therefore, chronic exposure to CP and UFP directly affects expression of disease-relevant genes in the myocardium.

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References

  • Aberle NS 2nd, Ren J (2003) Short-term acetaldehyde exposure depresses ventricular myocyte contraction: role of cytochrome P450 oxidase, xanthine oxidase, and lipid peroxidation. Alcohol Clin Exp Res 27:577–583

    CAS  Google Scholar 

  • Aboutabl ME, Zordoky BN, El-Kadi AO (2009) 3-methylcholanthrene and benzo(a)pyrene modulate cardiac cytochrome P450 gene expression and arachidonic acid metabolism in male Sprague Dawley rats. Br J Pharmacol 158:1808–1819

    Article  CAS  Google Scholar 

  • Araujo JA, Barajas B, Kleinman M, Wang XP, Bennett BJ, Gong KW, Navab M, Harkema J, Sioutas C, Lusis AJ, Nel AE (2008) Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress. Circ Res 102:589–596

    Article  CAS  Google Scholar 

  • Billet S, Garcon G, Dagher Z, Verdin A, Ledoux F, Cazier F, Courcot D, Aboukais A, Shirali P (2007) Ambient particulate matter (PM2.5): physicochemical characterization and metabolic activation of the organic fraction in human lung epithelial cells (A549). Environ Res 105:212–223

    Article  CAS  Google Scholar 

  • Bolt HM, Roos PH, Thier R (2003) The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals: consequences for occupational and environmental medicine. Int Arch Occup Environ Health 76:174–185

    CAS  Google Scholar 

  • Cassee FR, Muijser H, Duistermaat E, Freijer JJ, Geerse KB, Marijnissen JC, Arts JH (2002) Particle size-dependent total mass deposition in lungs determines inhalation toxicity of cadmium chloride aerosols in rats. Application of a multiple path dosimetry model. Arch Toxicol 76:277–286

    Article  CAS  Google Scholar 

  • Cho AK, Sioutas C, Miguel AH, Kumagai Y, Schmitz DA, Singh M, Eiguren-Fernandez A, Froines JR (2005) Redox activity of airborne particulate matter at different sites in the Los Angeles Basin. Environ Res 99:40–47

    Article  CAS  Google Scholar 

  • Donaldson K, Stone V, Seaton A, MacNee W (2001) Ambient particle inhalation and the cardiovascular system: potential mechanisms. Environ Health Perspect 4:523–527

    Article  Google Scholar 

  • Donaldson K, Brown D, Clouter A, Duffin R, MacNee W, Renwick L, Tran L, Stone V (2002) The pulmonary toxicology of ultrafine particles. J Aerosol Med 15:213–220

    Article  CAS  Google Scholar 

  • Du P, Kibbe WA, Lin SM (2007) nuID: a universal naming scheme of oligonucleotides for Illumina, Affymetrix, and other microarrays. Biol Direct 2:16

    Article  Google Scholar 

  • Fan H, Sun B, Gu Q, Lafond-Walker A, Cao S, Becker LC (2002) Oxygen radicals trigger activation of NF-kappaB and AP-1 and upregulation of ICAM-1 in reperfused canine heart. Am J Physiol Heart Circ Physiol 282:H1778–H1786

    CAS  Google Scholar 

  • Ghio AJ, Devlin RB (2001) Inflammatory lung injury after bronchial instillation of air pollution particles. Am J Respir Crit Care Med 164:704–708

    CAS  Google Scholar 

  • Gong KW, Zhao W, Li N, Barajas B, Kleinman M, Sioutas C, Horvath S, Lusis AJ, Nel A, Araujo JA (2007) Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells. Genome Biol 8:R149

    Article  Google Scholar 

  • Gorlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R (2001) Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: role of the p22(phox)-containing NADPH oxidase. Circ Res 89:47–54

    Article  CAS  Google Scholar 

  • Gurgueira SA, Lawrence J, Coull B, Murthy GG, Gonzalez-Flecha B (2002) Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation. Environ Health Perspect 110:749–755

    Article  CAS  Google Scholar 

  • Hoffmann B, Moebus S, Mohlenkamp S, Stang A, Lehmann N, Dragano N, Schmermund A, Memmesheimer M, Mann K, Erbel R, Jockel KH (2007) Residential exposure to traffic is associated with coronary atherosclerosis. Circulation 116:489–496

    Article  CAS  Google Scholar 

  • Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, Kim DK, Lee KW, Han PL, Rhee SG, Choi I (2000) Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol 164:6287–6295

    CAS  Google Scholar 

  • Kersten S (2005) Regulation of lipid metabolism via angiopoietin-like proteins. Biochem Soc Trans 33:1059–1062

    Article  CAS  Google Scholar 

  • Kim S, Jaques PA, Chang MC, Barone T, Xiong C, Friedlander SK, Sioutas C (2001a) Versatile Aerosol Concentration Enrichment System (VACES) for simultaneous in vivo and in vitro evaluation of toxic effects of ultrafine, fine and coarse ambient particles - Part II: Field evaluation. J Aerosol Sci 32:1299–1314

    Article  CAS  Google Scholar 

  • Kim S, Jaques PA, Chang MC, Froines JR, Sioutas C (2001b) Versatile Aerosol Concentration Enrichment System (VACES) for simultaneous in vivo and in vitro evaluation of toxic effects of ultrafine, fine and coarse ambient particles—Part I: Development and laboratory characterization. J Aerosol Sci 32:1281–1297

    Article  CAS  Google Scholar 

  • Kleinman MT, Hamade A, Meacher D, Oldham M, Sioutas C, Chakrabarti B, Stram D, Froines JR, Cho AK (2005) Inhalation of concentrated ambient particulate matter near a heavily trafficked road stimulates antigen-induced airway responses in mice. J Air Waste Manag Assoc 55:1277–1288

    CAS  Google Scholar 

  • Kunzli N, Jerrett M, Mack WJ, Beckerman B, LaBree L, Gilliland F, Thomas D, Peters J, Hodis HN (2005) Ambient air pollution and atherosclerosis in Los Angeles. Environ Health Perspect 113:201–206

    Article  CAS  Google Scholar 

  • Li N, Sioutas C, Cho A, Schmitz D, Misra C, Sempf J, Wang M, Oberley T, Froines J, Nel A (2003) Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage. Environ Health Perspect 111:455–460

    Article  CAS  Google Scholar 

  • Lieber CS (1997) Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev 77:517–544

    CAS  Google Scholar 

  • Lin SM, Du P, Huber W, Kibbe WA (2008) Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res 36:e11

    Article  Google Scholar 

  • Nemmar A, Hoet PH, Vanquickenborne B, Dinsdale D, Thomeer M, Hoylaerts MF, Vanbilloen H, Mortelmans L, Nemery B (2002a) Passage of inhaled particles into the blood circulation in humans. Circulation 105:411–414

    Article  CAS  Google Scholar 

  • Nemmar A, Hoylaerts MF, Hoet PH, Dinsdale D, Smith T, Xu H, Vermylen J, Nemery B (2002b) Ultrafine particles affect experimental thrombosis in an in vivo hamster model. Am J Respir Crit Care Med 166:998–1004

    Article  Google Scholar 

  • Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y, Yodoi J (1999) Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem 274:21645–21650

    Article  CAS  Google Scholar 

  • Ntziachristos L, Froines JR, Cho AK, Sioutas C (2007) Relationship between redox activity and chemical speciation of size-fractionated particulate matter. Part Fibre Toxicol 4:5

    Article  Google Scholar 

  • Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, Kreyling W, Cox C (2002) Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A 65:1531–1543

    Article  CAS  Google Scholar 

  • Patwari P, Higgins LJ, Chutkow WA, Yoshioka J, Lee RT (2006) The interaction of thioredoxin with Txnip. Evidence for formation of a mixed disulfide by disulfide exchange. J Biol Chem 281:21884–21891

    Article  CAS  Google Scholar 

  • Peters A, Dockery DW, Muller JE, Mittleman MA (2001) Increased particulate air pollution and the triggering of myocardial infarction. Circulation 103:2810–2815

    CAS  Google Scholar 

  • Pope CA 3rd, Dockery DW (2006) Health effects of fine particulate air pollution: lines that connect. J Air Waste Manag Assoc 56:709–742

    CAS  Google Scholar 

  • Pope CA 3rd, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ (2004) Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 109:71–77

    Article  Google Scholar 

  • Pope CA 3rd, Muhlestein JB, May HT, Renlund DG, Anderson JL, Horne BD (2006) Ischemic heart disease events triggered by short-term exposure to fine particulate air pollution. Circulation 114:2443–2448

    Article  CAS  Google Scholar 

  • Rahman I, Mulier B, Gilmour PS, Watchorn T, Donaldson K, Jeffery PK, MacNee W (2001) Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappaB. Biochem Pharmacol 62:787–794

    Article  CAS  Google Scholar 

  • Rhoden CR, Wellenius GA, Ghelfi E, Lawrence J, Gonzalez-Flecha B (2005) PM-induced cardiac oxidative stress and dysfunction are mediated by autonomic stimulation. Biochim Biophys Acta 1725:305–313

    CAS  Google Scholar 

  • Saint-Georges F, Abbas I, Billet S, Verdin A, Gosset P, Mulliez P, Shirali P, Garcon G (2008) Gene expression induction of volatile organic compound and/or polycyclic aromatic hydrocarbon-metabolizing enzymes in isolated human alveolar macrophages in response to airborne particulate matter (PM2.5). Toxicology 244:220–230

    Article  CAS  Google Scholar 

  • Schulze PC, Yoshioka J, Takahashi T, He Z, King GL, Lee RT (2004) Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein. J Biol Chem 279:30369–30374

    Article  CAS  Google Scholar 

  • Semenza GL (2000) Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest 106:809–812

    Article  CAS  Google Scholar 

  • Seo SK, Yang HI, Lee KE, Kim HY, Cho S, Choi YS, Lee BS (2000) The roles of thioredoxin and thioredoxin-binding protein-2 in endometriosis. Hum Reprod 25:1251–1258

    Article  Google Scholar 

  • Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4:E131–E136

    Article  CAS  Google Scholar 

  • Sidorik L, Kyyamova R, Bobyk V, Kapustian L, Rozhko O, Vigontina O, Ryabenko D, Danko I, Maksymchuk O, Kovalenko VN, Filonenko VV, Chaschin NA (2005) Molecular chaperone, HSP60, and cytochrome P450 2E1 co-expression in dilated cardiomyopathy. Cell Biol Int 29:51–55

    Article  CAS  Google Scholar 

  • Simkhovich BZ, Kleinman MT, Kloner RA (2008) Air pollution and cardiovascular injury epidemiology, toxicology, and mechanisms. J Am Coll Cardiol 52:719–726

    Article  CAS  Google Scholar 

  • Smyth GK (2004) Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. In: Smyth GK (ed) Statistical Applications in Genetics and Molecular Biology, Article 3. Berkeley Electronic Press, Berkeley, CA

    Google Scholar 

  • Somers CM, McCarry BE, Malek F, Quinn JS (2004) Reduction of particulate air pollution lowers the risk of heritable mutations in mice. Science 304:1008–1010

    Article  CAS  Google Scholar 

  • Sugden MC, Bulmer K, Holness MJ (2001) Fuel-sensing mechanisms integrating lipid and carbohydrate utilization. Biochem Soc Trans 29:272–278

    Article  CAS  Google Scholar 

  • Thier R, Lewalter J, Selinski S, Bolt HM (2002) Possible impact of human CYP2E1 polymorphisms on the metabolism of acrylonitrile. Toxicol Lett 128:249–255

    Article  CAS  Google Scholar 

  • Thum T, Borlak J (2000a) Cytochrome P450 mono-oxygenase gene expression and protein activity in cultures of adult cardiomyocytes of the rat. Br J Pharmacol 130:1745–1752

    Article  CAS  Google Scholar 

  • Thum T, Borlak J (2000b) Gene expression in distinct regions of the heart. Lancet 355:979–983

    Article  CAS  Google Scholar 

  • Valen G, Yan ZQ, Hansson GK (2001) Nuclear factor kappa-B and the heart. J Am Coll Cardiol 38:307–314

    Article  CAS  Google Scholar 

  • van Leeuwen DM, van Herwijnen MH, Pedersen M, Knudsen LE, Kirsch-Volders M, Sram RJ, Staal YC, Bajak E, van Delft JH, Kleinjans JC (2006) Genome-wide differential gene expression in children exposed to air pollution in the Czech Republic. Mutat Res 600:12–22

    Google Scholar 

  • von Klot S, Peters A, Aalto P, Bellander T, Berglind N, D'Ippoliti D, Elosua R, Hormann A, Kulmala M, Lanki T, Lowel H, Pekkanen J, Picciotto S, Sunyer J, Forastiere F (2005) Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities. Circulation 112:3073–3079

    Article  Google Scholar 

  • Wellenius GA, Schwartz J, Mittleman MA (2006) Particulate air pollution and hospital admissions for congestive heart failure in seven United States cities. Am J Cardiol 97:404–408

    Article  CAS  Google Scholar 

  • World CJ, Yamawaki H, Berk BC (2006) Thioredoxin in the cardiovascular system. J Mol Med 84:997–1003

    Article  CAS  Google Scholar 

  • Wu D, Cederbaum AI (2005) Oxidative stress mediated toxicity exerted by ethanol-inducible CYP2E1. Toxicol Appl Pharmacol 207:70–76

    Article  Google Scholar 

  • Xu A, Lam MC, Chan KW, Wang Y, Zhang J, Hoo RL, Xu JY, Chen B, Chow WS, Tso AW, Lam KS (2005) Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc Natl Acad Sci USA 102:6086–6091

    Article  CAS  Google Scholar 

  • Yoshida K, Shimizugawa T, Ono M, Furukawa H (2002) Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J Lipid Res 43:1770–1772

    Article  CAS  Google Scholar 

  • Yoshioka J, Schulze PC, Cupesi M, Sylvan JD, MacGillivray C, Gannon J, Huang H, Lee RT (2004) Thioredoxin-interacting protein controls cardiac hypertrophy through regulation of thioredoxin activity. Circulation 109:2581–2586

    Article  CAS  Google Scholar 

  • Yoshioka J, Imahashi K, Gabel SA, Chutkow WA, Burds AA, Gannon J, Schulze PC, MacGillivray C, London RE, Murphy E, Lee RT (2007) Targeted deletion of thioredoxin-interacting protein regulates cardiac dysfunction in response to pressure overload. Circ Res 101:1328–1338

    Article  CAS  Google Scholar 

  • Zhao XQ, Zhao JJ, Li XY, Zhang Y, Jiao XY (2010) The change of thioredoxin system in myocardial tissue of type 2 diabetic rats undergoing myocardial injury. Sheng Li Xue Bao 62:261–268

    CAS  Google Scholar 

  • Zhu YF, Hinds WC, Kim S, Shen S, Sioutas C (2002) Study of ultrafine particles near a major highway with heavy-duty diesel traffic. Atmos Environ 36:4323–4335

    Article  CAS  Google Scholar 

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Acknowledgement

This work was supported by the US Environmental Protection Agency (USEPA) STAR Grant No. RD-83195201 and by the Gwladys and John Zurlo Charitable Foundation.

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Authors and Affiliations

  1. Heart Institute, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angeles, CA, 90017, USA

    Boris Z. Simkhovich & Robert A. Kloner

  2. Division of Cardiovascular Medicine, Keck School of Medicine, Los Angeles, CA, USA

    Boris Z. Simkhovich & Robert A. Kloner

  3. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Ruty Mehrian-Shai & Ya-Hsuan Hsu

  4. Division of Occupational and Environmental Medicine, University of California-Irvine, Irvine, CA, USA

    Michael T. Kleinman, Dianne Meacher, Glenn Gookin, Michael Mac Kinnon, Karina Salazar & Paul Willet

  5. Biomedical Informatics Center, Northwestern University, Chicago, IL, USA

    Gang Feng & Simon M. Lin

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  1. Boris Z. Simkhovich
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  2. Michael T. Kleinman
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  3. Ruty Mehrian-Shai
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Correspondence to Boris Z. Simkhovich.

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Simkhovich, B.Z., Kleinman, M.T., Mehrian-Shai, R. et al. Chronic exposure to ambient particulate matter alters cardiac gene expression patterns and markers of oxidative stress in rats. Air Qual Atmos Health 4, 15–25 (2011). https://doi.org/10.1007/s11869-010-0089-0

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