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Cardiovascular Toxicology

, Volume 7, Issue 4, pp 264–272 | Cite as

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

  • Xabier Arzuaga
  • Gudrun Reiterer
  • Zuzana Majkova
  • Michael W. Kilgore
  • Michal Toborek
  • Bernhard HennigEmail author
Article

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.

Keywords

Atherosclerosis Vascular endothelial cells PPARα PPARγ PCB AHR CYP1A1 VCAM-1 COX-2 Inflammation 

Notes

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.

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 6.
    Lusis, A. J. (2000). Atherosclerosis. Nature, 407, 233–241.CrossRefPubMedGoogle Scholar
  7. 7.
    Libby, P. (2002). Inflammation in atherosclerosis. Nature, 420, 868–874.CrossRefPubMedGoogle Scholar
  8. 8.
    Slim, R., Toborek, M., Robertson, L. W., & Hennig, B. (1999). Antioxidant protection against PCB-mediated endothelial cell activation. Toxicological Sciences, 52, 232–239.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 13.
    Ross, R. (1999). Atherosclerosis—an inflammatory disease. The New England Journal of Medicine, 340, 115–126.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 19.
    Issemann, I., & Green, S. (1990). Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 347, 645–650.CrossRefPubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 24.
    Delerive, P., Fruchart, J. C., & Staels, B. (2001). Peroxisome proliferator-activated receptors in inflammation control. The Journal of Endocrinology, 169, 453–459.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 26.
    Jensen, A. A. (1989). Halogenated biphenyls, terphenyls, naphthalenes, dibenzodioxins and related products. Amsterdam: Elsevier Science Publishers.Google Scholar
  27. 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.PubMedGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 30.
    Whitlock, J. P., Jr. (1999). Induction of cytochrome P4501A1. Annual Review of Pharmacology and Toxicology, 39, 103–125.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 33.
    Leopold, J. A., & Loscalzo, J. (2005). Oxidative enzymopathies and vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 1332–1340.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.CrossRefPubMedGoogle Scholar
  48. 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.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 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.CrossRefPubMedGoogle Scholar
  51. 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.CrossRefPubMedGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 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.Google Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. 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.CrossRefPubMedGoogle Scholar
  56. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Xabier Arzuaga
    • 1
  • Gudrun Reiterer
    • 1
    • 2
  • Zuzana Majkova
    • 1
  • Michael W. Kilgore
    • 3
  • Michal Toborek
    • 2
    • 4
  • Bernhard Hennig
    • 1
    • 2
    Email author
  1. 1.Molecular and Cell Nutrition Laboratory, College of AgricultureUniversity of KentuckyLexingtonUSA
  2. 2.Graduate Center for Nutritional SciencesUniversity of KentuckyLexingtonUSA
  3. 3.Department of PharmacologyUniversity of KentuckyLexingtonUSA
  4. 4.Department of NeurosurgeryUniversity of KentuckyLexingtonUSA

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