Skip to main content

Advertisement

SpringerLink
Log in

PPARα Ligands Reduce PCB-Induced Endothelial Activation: Possible Interactions in Inflammation and Atherosclerosis

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Exposure to polychlorinated biphenyls (PCBs) can activate inflammatory responses in vascular endothelial cells. Activation of peroxisome proliferator-activated receptors (PPARs) by nutrients or synthetic agonists has been shown to block pro-inflammatory responses both in vitro and in vivo. Here we demonstrate that activation of PPARα by synthetic agonists can reduce 3,3′4,4′-tetrachlorobiphenyl (PCB77)-induced endothelial cell activation. Primary vascular endothelial cells were pretreated with the PPARα ligands fenofibrate or WY14643 followed by exposure to PCB77. PPARα activation protected endothelial cells against PCB77-induced expression of the pro-inflammatory proteins vascular cell adhesion molecule-1 (VCAM-1), cycloxygenase-2 (COX-2), and PCB77-induced expression and activity of the aryl hydrocarbon receptor (AHR) responsive cytochrome P450 1A1 (CYP1A1). Furthermore, basal AHR expression was downregulated by fenofibrate and WY14643. We also investigated the possible interactions between PCBs, and basal PPAR activity and protein expression. Treatment with PCB77 significantly reduced basal mRNA expression of PPARα and the PPAR responsive gene CYP4A1, as well as PPARα protein expression. Also, PCB77 exposure caused a significant decrease in basal PPAR-dependent reporter gene expression in MCF-7 cells. Overall, these findings suggest that PPARα agonists can reduce PCB77 induction of endothelial cell activation by inhibition of the AHR pathway, and that coplanar PCB induced pro-inflammatory effects could be mediated, in part, by inhibition of PPARα expression and function.

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
Fig. 7

Similar content being viewed by others

References

  1. Gustavsson, P., & Hogstedt, C. (1997). A cohort study of Swedish capacitor manufacturing workers exposed to polychlorinated biphenyls (PCBs). American Journal of Industrial Medicine, 32, 234–239.

    Article  CAS  PubMed  Google Scholar 

  2. Pelclova, D., Fenclova, Z., Preiss, J., Prochazka, B., Spacil, J., Dubska, Z., Okrouhlik, B., Lukas, E., & Urban, P. (2002). Lipid metabolism and neuropsychological follow-up study of workers exposed to 2,3,7,8- tetrachlordibenzo-p-dioxin. International Archives of Occupational and Environmental Health, 75(Suppl), S60–S66.

    CAS  PubMed  Google Scholar 

  3. Bertazzi, P. A., Bernucci, I., Brambilla, G., Consonni, D., & Pesatori, A. C. (1998). The Seveso studies on early and long-term effects of dioxin exposure: A review. Environmental Health Perspectives, 106(Suppl 2), 625–633.

    Article  CAS  PubMed  Google Scholar 

  4. Pesatori, A. C., Zocchetti, C., Guercilena, S., Consonni, D., Turrini, D., & Bertazzi, P. A. (1998). Dioxin exposure and non-malignant health effects: A mortality study. Occupational and Environmental Medicine, 55, 126–131.

    Article  CAS  PubMed  Google Scholar 

  5. Sergeev, A. V., & Carpenter, D. O. (2005). Hospitalization rates for coronary heart disease in relation to residence near areas contaminated with persistent organic pollutants and other pollutants. Environmental Health Perspectives, 113, 756–761.

    Article  CAS  PubMed  Google Scholar 

  6. Lusis, A. J. (2000). Atherosclerosis. Nature, 407, 233–241.

    Article  CAS  PubMed  Google Scholar 

  7. Libby, P. (2002). Inflammation in atherosclerosis. Nature, 420, 868–874.

    Article  CAS  PubMed  Google Scholar 

  8. Slim, R., Toborek, M., Robertson, L. W., & Hennig, B. (1999). Antioxidant protection against PCB-mediated endothelial cell activation. Toxicological Sciences, 52, 232–239.

    Article  CAS  PubMed  Google Scholar 

  9. Hennig, B., Meerarani, P., Slim, R., Toborek, M., Daugherty, A., Silverstone, A. E., & Robertson, L. W. (2002). Proinflammatory properties of coplanar PCBs: In vitro and in vivo evidence. Toxicology and Applied Pharmacology, 181, 174–183.

    Article  CAS  PubMed  Google Scholar 

  10. Kougias, P., Chai, H., Lin, P. H., Yao, Q., Lumsden, A. B., & Chen, C. (2005). Effects of adipocyte-derived cytokines on endothelial functions: Implication of vascular disease. The Journal of Surgical Research, 126, 121–129.

    Article  CAS  PubMed  Google Scholar 

  11. Colombo, P. C., Banchs, J. E., Celaj, S., Talreja, A., Lachmann, J., Malla, S., DuBois, N. B., Ashton, A. W., Latif, F., Jorde, U. P., Ware, J. A., & LeJemtel, T. H. (2005). Endothelial cell activation in patients with decompensated heart failure. Circulation, 111, 58–62.

    Article  CAS  PubMed  Google Scholar 

  12. Vogel, C. F., Sciullo, E., & Matsumura, F. (2004). Activation of inflammatory mediators and potential role of ah-receptor ligands in foam cell formation. Cardiovascular Toxicology, 4, 363–373.

    Article  CAS  PubMed  Google Scholar 

  13. Ross, R. (1999). Atherosclerosis—an inflammatory disease. The New England Journal of Medicine, 340, 115–126.

    Article  CAS  PubMed  Google Scholar 

  14. Ramadass, P., Meerarani, P., Toborek, M., Robertson, L. W., & Hennig, B. (2003). Dietary flavonoids modulate PCB-induced oxidative stress, CYP1A1 induction, and AhR-DNA binding activity in vascular endothelial cells. Toxicological Sciences, 76, 212–219.

    Article  CAS  PubMed  Google Scholar 

  15. Matsumura, F. (2003). On the significance of the role of cellular stress response reactions in the toxic actions of dioxin. Biochemical Pharmacology, 66, 527–540.

    Article  CAS  PubMed  Google Scholar 

  16. Shertzer, H. G., Nebert, D. W., Puga, A., Ary, M., Sonntag, D., Dixon, K., Robinson, L. J., Cianciolo, E., & Dalton, T. P. (1998). Dioxin causes a sustained oxidative stress response in the mouse. Biochemical and Biophysical Research Communications, 253, 44–48.

    Article  CAS  PubMed  Google Scholar 

  17. Celander, M., & Forlin, L. (1995). Decreased responsiveness of the hepatic cytochrome-P450 1a1 system in rainbow-trout (Oncorhynchus-Mykiss) after prolonged exposure to Pcb. Aquatic Toxicology, 33, 141–153.

    Article  CAS  Google Scholar 

  18. Hennig, B., Ettinger, A. S., Jandacek, R. J., Koo, S., McClain, C., Seifried, H., Silverstone, A., Watkins, B., & Suk, W. A. (2007). Using nutrition for intervention and prevention against environmental chemical toxicity and associated diseases. Environmental Health Perspectives, 115, 493–495.

    Article  CAS  PubMed  Google Scholar 

  19. Issemann, I., & Green, S. (1990). Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 347, 645–650.

    Article  CAS  PubMed  Google Scholar 

  20. Tugwood, J. D., Issemann, I., Anderson, R. G., Bundell, K. R., McPheat, W. L., & Green, S. (1992). The mouse peroxisome proliferator activated receptor recognizes a response element in the 5′ flanking sequence of the rat acyl CoA oxidase gene. The EMBO Journal, 11, 433–439.

    CAS  PubMed  Google Scholar 

  21. Israelian-Konaraki, Z., & Reaven, P. D. (2005). Peroxisome proliferator-activated receptor-alpha and atherosclerosis: From basic mechanisms to clinical implications. Cardiology, 103, 1–9.

    Article  PubMed  CAS  Google Scholar 

  22. Mishra, A., Chaudhary, A., & Sethi, S. (2004). Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 1621–1627.

    Article  CAS  PubMed  Google Scholar 

  23. Zambon, A., Gervois, P., Pauletto, P., Fruchart, J. C., & Staels, B. (2006). Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators: Clinical and experimental evidence. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 977–986.

    Article  CAS  PubMed  Google Scholar 

  24. Delerive, P., Fruchart, J. C., & Staels, B. (2001). Peroxisome proliferator-activated receptors in inflammation control. The Journal of Endocrinology, 169, 453–459.

    Article  CAS  PubMed  Google Scholar 

  25. Toborek, M., Lee, Y. W., Kaiser, S., & Hennig, B. (2002). Measurement of inflammatory properties of fatty acids in human endothelial cells. Methods in Enzymology, 352, 198–219.

    Article  CAS  PubMed  Google Scholar 

  26. Jensen, A. A. (1989). Halogenated biphenyls, terphenyls, naphthalenes, dibenzodioxins and related products. Amsterdam: Elsevier Science Publishers.

    Google Scholar 

  27. Stegeman, J. J., Hahn, M. E., Weisbrod, R., Woodin, B. R., Joy, J. S., Najibi, S., & Cohen, R. A. (1995). Induction of cytochrome P4501A1 by aryl hydrocarbon receptor agonists in porcine aorta endothelial cells in culture and cytochrome P4501A1 activity in intact cells. Molecular Pharmacology, 47, 296–306.

    CAS  PubMed  Google Scholar 

  28. Kilgore, M. W., Tate, P. L., Rai, S., Sengoku, E., & Price, T. M. (1997). MCF-7 and T47D human breast cancer cells contain a functional peroxisomal response. Molecular and Cell Endocrinology, 129, 229–235.

    Article  CAS  Google Scholar 

  29. Korashy, H. M., & El-Kadi, A. O. (2006). The role of aryl hydrocarbon receptor in the pathogenesis of cardiovascular diseases. Drug Metabolism Reviews, 38, 411–450.

    Article  CAS  PubMed  Google Scholar 

  30. Whitlock, J. P., Jr. (1999). Induction of cytochrome P4501A1. Annual Review of Pharmacology and Toxicology, 39, 103–125.

    Article  CAS  PubMed  Google Scholar 

  31. Morishima, A., Ohkubo, N., Maeda, N., Miki, T., & Mitsuda, N. (2003). NFkappaB regulates plasma apolipoprotein A-I and high density lipoprotein cholesterol through inhibition of peroxisome proliferator-activated receptor alpha. The Journal of Biological Chemistry, 278, 38188–38193.

    Article  CAS  PubMed  Google Scholar 

  32. Reynders, V., Loitsch, S., Steinhauer, C., Wagner, T., Steinhilber, D., & Bargon, J. (2006). Peroxisome proliferator-activated receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes. Respiratory Research, 7, 104.

    Article  PubMed  CAS  Google Scholar 

  33. Leopold, J. A., & Loscalzo, J. (2005). Oxidative enzymopathies and vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 1332–1340.

    Article  CAS  PubMed  Google Scholar 

  34. Burleigh, M. E., Babaev, V. R., Oates, J. A., Harris, R. C., Gautam, S., Riendeau, D., Marnett, L. J., Morrow, J. D., Fazio, S., & Linton, M. F. (2002). Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation, 105, 1816–1823.

    Article  CAS  PubMed  Google Scholar 

  35. Puga, A., Hoffer, A., Zhou, S., Bohm, J. M., Leikauf, G. D., & Shertzer, H. G. (1997). Sustained increase in intracellular free calcium and activation of cyclooxygenase-2 expression in mouse hepatoma cells treated with dioxin. Biochemical Pharmacology, 54, 1287–1296.

    Article  CAS  PubMed  Google Scholar 

  36. Delerive, P., Martin-Nizard, F., Chinetti, G., Trottein, F., Fruchart, J. C., Najib, J., Duriez, P., & Staels, B. (1999). Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circulation Research, 85, 394–402.

    CAS  PubMed  Google Scholar 

  37. Delerive, P., Gervois, P., Fruchart, J. C., & Staels, B. (2000). Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. The Journal of Biological Chemistry, 275, 36703–36707.

    Article  CAS  PubMed  Google Scholar 

  38. Kleemann, R., Gervois, P. P., Verschuren, L., Staels, B., Princen, H. M., & Kooistra, T. (2003). Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation. Blood, 101, 545–551.

    Article  CAS  PubMed  Google Scholar 

  39. Gervois, P., Kleemann, R., Pilon, A., Percevault, F., Koenig, W., Staels, B., & Kooistra, T. (2004). Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate. The Journal of Biological Chemistry, 279, 16154–16160.

    Article  CAS  PubMed  Google Scholar 

  40. Shaban, Z., El-Shazly, S., Ishizuka, M., Kimura, K., Kazusaka, A., & Fujita, S. (2004). PPARalpha-dependent modulation of hepatic CYP1A by clofibric acid in rats. Archives of Toxicology, 78, 496–507.

    Article  CAS  PubMed  Google Scholar 

  41. Andrysik, Z., Vondracek, J., Machala, M., Krcmar, P., Svihalkova-Sindlerova, L., Kranz, A., Weiss, C., Faust, D., Kozubik, A., & Dietrich, C. (2007). The aryl hydrocarbon receptor-dependent deregulation of cell cycle control induced by polycyclic aromatic hydrocarbons in rat liver epithelial cells. Mutation Research, 615, 87–97.

    CAS  PubMed  Google Scholar 

  42. Fallone, F., Villard, P. H., Decome, L., Seree, E., Meo, M., Chacon, C., Durand, A., Barra, Y., & Lacarelle, B. (2005). PPARalpha activation potentiates AhR-induced CYP1A1 expression. Toxicology, 216, 122–128.

    Article  CAS  PubMed  Google Scholar 

  43. Hanlon, P. R., Ganem, L. G., Cho, Y. C., Yamamoto, M., & Jefcoate, C. R. (2003). AhR- and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-gamma1 expression and subsequent adipocyte differentiation. Toxicology and Applied Pharmacology, 189, 11–27.

    Article  CAS  PubMed  Google Scholar 

  44. Alexander, D. L., Ganem, L. G., Fernandez-Salguero, P., Gonzalez, F., & Jefcoate, C. R. (1998). Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis. Journal of Cell Science, 111(Pt 22), 3311–3322.

    CAS  PubMed  Google Scholar 

  45. Hennig, B., Reiterer, G., Majkova, Z., Oesterling, E., Meerarani, P., & Toborek, M. (2005). Modification of environmental toxicity by nutrients: Implications in atherosclerosis. Cardiovascular Toxicology, 5, 153–160.

    Article  CAS  PubMed  Google Scholar 

  46. Cimafranca, M. A., Hanlon, P. R., & Jefcoate, C. R. (2004). TCDD administration after the pro-adipogenic differentiation stimulus inhibits PPARgamma through a MEK-dependent process but less effectively suppresses adipogenesis. Toxicology and Applied Pharmacology, 196, 156–168.

    Article  CAS  PubMed  Google Scholar 

  47. Poynter, M. E., & Daynes, R. A. (1998). Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. The Journal of Biological Chemistry, 273, 32833–32841.

    Article  CAS  PubMed  Google Scholar 

  48. El Midaoui, A., Wu, L., Wang, R., & de Champlain, J. (2006). Modulation of cardiac and aortic peroxisome proliferator-activated receptor-gamma expression by oxidative stress in chronically glucose-fed rats. American Journal of Hypertension, 19, 407–412.

    Article  CAS  PubMed  Google Scholar 

  49. Kim, M. S., Sweeney, T. R., Shigenaga, J. K., Chui, L. G., Moser, A., Grunfeld, C., & Feingold, K. R. (2007). Tumor necrosis factor and interleukin 1 decrease RXRalpha, PPARalpha, PPARgamma, LXRalpha, and the coactivators SRC-1, PGC-1alpha, and PGC-1beta in liver cells. Metabolism, 56, 267–279.

    Article  CAS  PubMed  Google Scholar 

  50. Gearing, K. L., Crickmore, A., & Gustafsson, J. A. (1994). Structure of the mouse peroxisome proliferator activated receptor alpha gene. Biochemical and Biophysical Research Communications, 199, 255–263.

    Article  CAS  PubMed  Google Scholar 

  51. Chew, C. H., Samian, M. R., Najimudin, N., & Tengku-Muhammad, T. S. (2003). Molecular characterisation of six alternatively spliced variants and a novel promoter in human peroxisome proliferator-activated receptor alpha. Biochemical and Biophysical Research Communications, 305, 235–43.

    Article  CAS  PubMed  Google Scholar 

  52. Khan, S., Barhoumi, R., Burghardt, R., Liu, S., Kim, K., & Safe, S. (2006). Molecular mechanism of inhibitory aryl hydrocarbon receptor-estrogen receptor/Sp1 cross talk in breast cancer cells. Molecular Endocrinology, 20, 2199–2214.

    Article  CAS  PubMed  Google Scholar 

  53. Tsuchiya, Y., Nakajima, M., & Yokoi, T. (2003). Critical enhancer region to which AhR/ARNT and Sp1 bind in the human CYP1B1 gene. Journal of Biochemistry (Tokyo), 133, 583–592.

    CAS  Google Scholar 

  54. Delerive, P., De Bosscher, K., Besnard, S., Vanden Berghe, W., Peters, J. M., Gonzalez, F. J., Fruchart, J. C., Tedgui, A., Haegeman, G., & Staels, B. (1999). Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. The Journal of Biological Chemistry, 274, 32048–32054.

    Article  CAS  PubMed  Google Scholar 

  55. Nakajima, A., Wada, K., Miki, H., Kubota, N., Nakajima, N., Terauchi, Y., Ohnishi, S., Saubermann, L. J., Kadowaki, T., Blumberg, R. S., Nagai, R., & Matsuhashi, N. (2001). Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury. Gastroenterology, 120, 460–469.

    Article  CAS  PubMed  Google Scholar 

  56. Corti, R., Osende, J., Hutter, R., Viles-Gonzalez, J. F., Zafar, U., Valdivieso, C., Mizsei, G., Fallon, J. T., Fuster, V., & Badimon, J. J. (2007). Fenofibrate induces plaque regression in hypercholesterolemic atherosclerotic rabbits: In vivo demonstration by high-resolution MRI. Atherosclerosis, 190, 106–113.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by grants from NIEHS/NIH (ES 07380), the KY AES, and the University of Kentucky Lyman T. Johnson Postdoctoral Fellowship. G. Reiterer is a recipient of the American Heart Association predoctoral fellowship.

Author information

Authors and Affiliations

  1. Molecular and Cell Nutrition Laboratory, College of Agriculture, University of Kentucky, Lexington, KY, 40536-0200, USA

    Xabier Arzuaga, Gudrun Reiterer, Zuzana Majkova & Bernhard Hennig

  2. Graduate Center for Nutritional Sciences, University of Kentucky, 591 Wethington Health Sciences Bldg, 900 South Limestone Street, Lexington, KY, 40536-0200, USA

    Gudrun Reiterer, Michal Toborek & Bernhard Hennig

  3. Department of Pharmacology, University of Kentucky, Lexington, KY, 40536-0200, USA

    Michael W. Kilgore

  4. Department of Neurosurgery, University of Kentucky, Lexington, KY, 40536-0200, USA

    Michal Toborek

Authors
  1. Xabier Arzuaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gudrun Reiterer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zuzana Majkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael W. Kilgore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michal Toborek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bernhard Hennig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernhard Hennig.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arzuaga, X., Reiterer, G., Majkova, Z. et al. PPARα Ligands Reduce PCB-Induced Endothelial Activation: Possible Interactions in Inflammation and Atherosclerosis. Cardiovasc Toxicol 7, 264–272 (2007). https://doi.org/10.1007/s12012-007-9005-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-007-9005-8

Keywords

Search

Navigation