Skip to main content
SpringerLink
Log in

Activation of group IVC phospholipase A2 by polycyclic aromatic hydrocarbons induces apoptosis of human coronary artery endothelial cells

  • Molecular Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Exposure to environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs) found in coal tar mixtures and tobacco sources, is considered a significant risk factor for the development of heart disease in humans. The goal of this study was to determine the influence of PAHs present at a Superfund site on human coronary artery endothelial cell (HCAEC) phospholipase A2 (PLA2) activity and apoptosis. Extremely high levels of 12 out of 15 EPA high-priority PAHs were present in both the streambed and floodplain sediments at a site where an urban creek and its adjacent floodplain were extensively contaminated by PAHs and other coal tar compounds. Nine of the 12 compounds and a coal tar mixture (SRM 1597A) activated group IVC PLA2 in HCAECs, and activation of this enzyme was associated with histone fragmentation and poly (ADP) ribose polymerase (PARP) cleavage. Genetic silencing of group IVC PLA2 inhibited both 3H-fatty acid release and histone fragmentation by PAHs and SRM 1597A, indicating that individual PAHs and a coal tar mixture induce apoptosis of HCAECs via a mechanism that involves group IVC PLA2. Western blot analysis of aortas isolated from feral mice (Peromyscus leucopus) inhabiting the Superfund site showed increased PARP and caspase-3 cleavage when compared to reference mice. These data suggest that PAHs induce apoptosis of HCAECs via activation of group IVC PLA2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Asai K, Hirabayashi T, Houjou T, Uozumi N, Taguchi R, Shimizu T (2003) Human group IVC phospholipase A2 (cPLA2gamma). Roles in the membrane remodeling and activation induced by oxidative stress. J Biol Chem 278:8809–8814

    Article  PubMed  CAS  Google Scholar 

  • Atsumi G, Tajima M, Hadano A, Nakatani Y, Murakami M, Kudo I (1998) Fas-induced arachidonic acid release is mediated by Ca2+-independent phospholipase A2, but not cytosolic phospholipase A2, which undergoes proteolytic inactivation. J Biol Chem 273:13870–13877

    Article  PubMed  CAS  Google Scholar 

  • Atsumi G, Murakami M, Kojima K, Hadano A, Tajima M, Kudo I (2000) Distinct roles of two intracellular phospholipase A2s in fatty acid release in the cell death pathway. J Biol Chem 275:18248–18258

    Article  PubMed  CAS  Google Scholar 

  • Bhat R, Bresnick E (1997) Glycine N-methyltransferase is an example of functional diversity: role as a polycyclic aromatic hydrocarbon-binding receptor. J Biol Chem 272:21221–21226

    Article  PubMed  CAS  Google Scholar 

  • Blaha L, Machala M, Vondracek J, Breinekova K (2001) Multiple oxidative stress parameters are modulated in vitro by oxygenated polycyclic aromatic hydrocarbons identified in river sediments. Adv Exp Med Biol 500:225–228

    PubMed  CAS  Google Scholar 

  • Blaha L, Kapplova P, Vondracek J, Upham B, Machala M (2002) Inhibition of gap-junctional intercellular communication by environmentally occurring polycyclic aromatic hydrocarbons. Toxicol Sci 65:43–51

    Article  PubMed  CAS  Google Scholar 

  • Capper EA, Marshall LA (2001) Mammalian phospholipase A(2): mediators of inflammation, proliferation and apoptosis. Prog Lipid Res 40:167–197

    Article  PubMed  CAS  Google Scholar 

  • Chaloupka K, Steinberg M, Santostefano M, Rodriguez LV, Goldstein L, Safe S (1995) Induction of cyp1a–1 and cyp1a–2 gene expression by a reconstituted mixture of polynuclear aromatic hydrocarbons in B6C3F1 mice. Chem Biol Ineract 96:207–221

    Article  CAS  Google Scholar 

  • Chang CS, Liao SS (1987) Topographic recognition of cyclic hydrocarbon and related compounds by receptors for androgens, estrogens and glucocorticoids. J Steroid Biochem 27(1–3):123–131

    Article  PubMed  CAS  Google Scholar 

  • Dana R, Malech HL, Levy R (1994) The requirement for phospholipase A2 for activation of the assembled NADPH oxidase in human neutrophils. Biochem J 297(pt 1):217–223

    PubMed  CAS  Google Scholar 

  • Davis WR (1992) Chattanooga Creek sediment profile study, Chattanooga, Tennessee. United States environmental protection agency, region IV, April/August 1992

  • Dimmeler S, Hermann C, Zeiher AM (1998) Apoptosis of endothelial cells. Contribution to the patho-physiology of atherosclerosis? Eur Cytokine Netw 9:697–698

    PubMed  CAS  Google Scholar 

  • Donaldson K, Stone V, Seaton A, MacNee W (2001) Ambient particle inhalation and the cardiovascular system: potential mechanisms. Environ Health Perspect 109(suppl 4):523–527

    Article  PubMed  CAS  Google Scholar 

  • Duan L, Gan H, Arm J, Remold HG (2001) Cytosolic phospholipase A2 participates with TNF-a in the induction of apoptosis of human macrophages infected with Mycobacterium tuberculosis H37Ra. J Immunol 166:7469–7476

    PubMed  CAS  Google Scholar 

  • Geng YJ, Libby P (1995) Evidence for apoptosis in advanced human atheroma: colocalization with interleukin-1β converting enzyme. Am J Pathol 147:251–266

    PubMed  CAS  Google Scholar 

  • Goodnight SH (1994) The vascular effects of ω-3 fatty acids. J Invest Dermatol 93:102S–106S

    Article  Google Scholar 

  • Granberg L, Brunstrom B, Brandt I (2003) Formation of benzo[a]pyrene and 7, 12-dimethylbenz[a]anthracene adducts in vascular endothelia of cytochrome P4501A-induced chicken embryos. Environ Toxicol Chem 22(10):2393–2399

    Article  PubMed  CAS  Google Scholar 

  • Hermann C, Zeiher AM, Dimmeler S (1997) Shear stress inhibits H2O2-induced apoptosis of human endothelial cells by modulation of the glutathione redox cycle and nitric oxide synthase. Arterioscler Thromb Vasc Biol 17:3588–3592

    PubMed  CAS  Google Scholar 

  • Howard G, Wagenknecht LE, Burke GL, Diez-Roux A, Evans GW, McGovern P, Nieto FJ, Tell GS (1998) Cigarette smoking and progression of atherosclerosis: the atherosclerosis risk in communities (ARIC) study. J Am Med Assoc 279:119–124

    Article  CAS  Google Scholar 

  • Isner JM, Kearney M, Bortman S, Passeri J (1995) Apoptosis in human atherosclerosis and restenosis. Circulation 91:2703–2711

    PubMed  CAS  Google Scholar 

  • IT Corporation (1999) Final report: removal action for the tennessee products superfund site, Chattanooga, Tennessee. US army corps of engineers

  • Kerzee JK, Ramos KS (2000) Activation of c-Ha-ras by benzo(a)pyrene in vascular smooth muscle cells involves redox stress and aryl hydrocarbon receptor. Mol Pharmacol 58:152–158

    PubMed  CAS  Google Scholar 

  • Lio YC, Reynolds LJ, Balsinde J, Dennis EA (1996) Irreversible inhibition of Ca(2+)-independent phospholipase A2 by methyl arachidonoyl fluorophosphonate. Biochim Biophys Acta 1302:55–60

    Article  PubMed  Google Scholar 

  • Mackay D, Shiu WY, Ma KC (1992) Illustrated handbook of physical-chemical properties and environmental fate for organic chemicals, Vol I–IV. Lewis Chelsea, MI

  • Mahadevan B, Marston C, Dashwood W, Yonghai L, Pererira C, Baird W (2005) Effect of a standardized complex mixture derived from coal tar on the metabolic activation of carcinogenic polycyclic hydrocarbons in human cells in culture. Chem Res Toxicol 18:224–231

    Article  PubMed  CAS  Google Scholar 

  • McCarty MF (1996) Fish oil may be an antidote for the cardiovascular risk of smoking. Med Hypotheses 46:337–347

    Article  PubMed  CAS  Google Scholar 

  • Mueller JG, Chapman PJ, Pritchard PH (1989) Creosote-contaminated sites. Environ Sci Technol 23:1197–1201

    Article  CAS  Google Scholar 

  • Nebert DW, Roe AL, Dieter MZ, Solis WA, Yang Y, Dalton TP (2000) Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol 59:65–85

    Article  PubMed  CAS  Google Scholar 

  • Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (1997) Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973–979

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez BL, Sharp DS, Abbott RD, Burchfiel CM, Masaki K, Chyou PH, Huang B, Yano K, Curb JD (1996) Fish intake may limit the increase in risk of coronary heart disease morbidity and mortality among heavy smokers. The honolulu heart program. Circulation 94:952–956

    PubMed  CAS  Google Scholar 

  • Rummel AM, Trosko JE, Wilson MR, Upham BL (1999) Polycyclic aromatic hydrocarbons with bay-like regions inhibited gap junctional intercellular communication and stimulated MAPK activity. Toxicol Sci 49:232–240

    Article  PubMed  CAS  Google Scholar 

  • Soldani C, Scovassi AI (2002) Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis 7:321–328

    Article  PubMed  CAS  Google Scholar 

  • Stewart A, Ghosh M, Spencer DM, Leslie CC (2002) Enzymatic properties of human cytosolic phospholipase A2γ. J Biol Chem 277:29526–29536

    Article  PubMed  CAS  Google Scholar 

  • Tithof PK, Peters-Golden M, Ganey PE (1998) Distinct phospholipases A2 regulate release of arachidonic acid for eicosanoid production and superoxide anion generation in neutrophils. J Immunol 160:953–960

    PubMed  CAS  Google Scholar 

  • Tithof PK, Elgayyar M, Cho Y, Guan W, Fisher AB, Peters-Golden M (2002) Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A2-dependent mechanism. FASEB J 16:1463–1464

    PubMed  CAS  Google Scholar 

  • Trudeau SF, Maisonneuve FJ (2001) A method to determine cytochrome P4501A activity in wildlife microsomes. Canadian Wildlife Services, Hull, Quebec, Canada. Headquarters Technical Report 339E

  • Tucker DE, Stewart A, Nallan L, Bendale P, Ghomashchi F, Gelb MH, Leslie CC (2005) Group IVC cytosolic phospholipase A2g is farnesylated and palmitoylated in mammalian cells. J Lipid Res 46:2122–2133

    Article  PubMed  CAS  Google Scholar 

  • Upham BL, Weis LM, Trosko JE (1998) Modulated gap junctional intercellular communication as a biomarker pf AH epigenetic toxicity: structure-function relationship. Eviron Health Perspect 106:975–981

    CAS  Google Scholar 

  • Upham BL, Blaha L, Babica P, Park JS, Sovadinova I, idrotj C, Rummel AM, Weis M, Sai L, Tithof PK, Guzvic M, Vondracek J, Machala M, Trosko JE (2008) Tumor promoting properties of cigarette smoke prevalent polycyclic aromatic hydrocarbon as indicated by the inhibition of gap junctional intercellular communication via phosphatidyl choline-specific phospholipase C. Cancer Sci 99:696–705

    Article  PubMed  CAS  Google Scholar 

  • US EPA (1999) Remedial investigation report for the Tennessee products site, Chattanooga, Tennessee. In: Remedial planning activities at selected uncontrolled hazardous substance disposal sites for EPA Region IV. United States environmental protection agency, Region IV, EPA 68-W9-0056, February 1999

  • US EPA (2004a) Preliminary remediation goals. United States environmental protection agency, region 9. http://www.epa.gov/region9/waste/sfund/prg/index.html

  • US EPA (2004b) SW-846 Manual: test methods for evaluating solid wastes, physical/chemical methods. United States environmental protection agency, office of solid waste. http://www.epa.gov/epaoswer/hazwaste/test/sw846.htm

  • Vulava VM, McKay LD, McCarthy JF, Dickerson DS, Cooper L, Menn F (2004) Transport and deposition of coal tar contaminated sediments in an urban freshwater stream. Presented at Fourth World Congress of the Society of environmental toxicology and chemistry in Portland, Oregon, Nov 14–19

  • Weis LM, Rummel AM, Masten SJ, Trosko JE, Upham BL (1998) Bay or baylike regions of polycylic aromatic hydrocarbons were potent inhibitors of gap junctional intercellular communication. Environ Health Perspect 106:17–22

    Article  PubMed  CAS  Google Scholar 

  • Whyte JJ, Tillitt DE (2000) Ethoxyresorufin-O-deethylase (EROD) activity in fish as a biomarker of chemical exposure for use in the biomonitoring of environmental status and trends (BEST) program. Crit Rev Tox 30:347–570

    Article  CAS  Google Scholar 

  • Zupan LA, Weiss RH, Hazen SL, Parnas BL, Aston DW, Lennon PJ, Getman DP, Gross RW (1993) Structural determinants of haloenol lactone-mediated suicide inhibition of canine myocardial calcium-independent phospholipase A2. J Med Chem 36:95–100

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Special thanks to Misty Bailey and Anik Vasington for excellent technical assistance. This work was supported by the Waste Management and Education Institute at the University of Tennessee, American Heart Association Grant #0160264B, and NIH grants HL34303 and HL61378.

Author information

Authors and Affiliations

  1. Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, 37996-4545, USA

    Patricia K. Tithof & Mona A. Elgayyar

  2. Department of Biological and Environmental Sciences, University of Tennessee, Chattanooga, TN, 37403, USA

    Sean M. Richards

  3. Center for Environmental Biotechnology, University of Tennessee, Knoxville, TN, 37996, USA

    Patricia K. Tithof, Fu-Minn Menn, Vijay M. Vulava, Larry McKay, John Sanseverino & Gary Sayler

  4. Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO, 80206, USA

    Dawn E. Tucker & Christina C. Leslie

  5. Department of Biology, Texas A&M University, College Station, TX, 77843, USA

    Kim P. Lu

  6. Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, 40202, USA

    Kenneth S. Ramos

Authors
  1. Patricia K. Tithof
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sean M. Richards
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mona A. Elgayyar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fu-Minn Menn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vijay M. Vulava
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Larry McKay
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John Sanseverino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gary Sayler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dawn E. Tucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christina C. Leslie
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kim P. Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kenneth S. Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patricia K. Tithof.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tithof, P.K., Richards, S.M., Elgayyar, M.A. et al. Activation of group IVC phospholipase A2 by polycyclic aromatic hydrocarbons induces apoptosis of human coronary artery endothelial cells. Arch Toxicol 85, 623–634 (2011). https://doi.org/10.1007/s00204-010-0614-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-010-0614-9

Keywords

Search

Navigation