Advertisement

Inflammation

, Volume 37, Issue 1, pp 177–185 | Cite as

The Protective Effect of Fenofibrate Against TNF-α-Induced CD40 Expression through SIRT1-Mediated Deacetylation of NF-κB in Endothelial Cells

  • Weirong Wang
  • Ling Bai
  • Hu Qiao
  • Yanxiang Li
  • Lina Yang
  • Jiye Zhang
  • Rong Lin
  • Feng Ren
  • Jianfeng Zhang
  • Meixi Ji
Article

Abstract

Fenofibrate, as a lipid-lowering drug in clinic, participates in the regulation of inflammatory response. Recently, increasing studies have indicated that sirtuin1 (SIRT1), a NAD+-dependent deacetylase, has potential anti-inflammatory effect in endothelial cells. However, whether the regulatory effect of fenofibrate on inflammation response is mediated by SIRT1 remains unclear. The aim of this study was to investigate the effect of fenofibrate on the expressions of SIRT1 and pro-inflammatory cytokine CD40 in endothelial cells and explore the underlying mechanisms. The results showed that fenofibrate upregulated SIRT1 expression and inhibited CD40 expression in TNF-α-stimulated endothelial cells, but these effects were reversed by peroxisome proliferator-activated receptor-α (PPARα) antagonist GW6471. Furthermore, SIRT1 inhibitors sirtinol/nicotinamide (NAM) or SIRT1 knockdown could attenuate the effect of fenofibrate on CD40 expression in endothelial cells. Importantly, NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) augmented the effect of fenofibrate on CD40 expression. Further study found that fenofibrate decreased the expression of acetylated-NF-κB p65 (Ac-NF-κB p65) in TNF-α-stimulated endothelial cells, which was abolished by SIRT1 knockdown. These results indicate that fenofibrate has protective effect against TNF-α-induced CD40 expression through SIRT1-mediated deacetylation of the p65 subunit of NF-κB.

KEY WORDS

fenofibrate SIRT1 NF-κB CD40 endothelial cells 

Notes

Acknowledgment

This study was supported by National Natural Science Foundation of China (Nos. 81072643 and 81270347) and Natural Science Foundation of Shaanxi Province (2012JQ4025).

Conflict of Interest

None.

References

  1. 1.
    Madej, A., B. Okopien, J. Kowalski, M. Zielinski, J. Wysocki, B. Szygula, Z. Kalina, and Z.S. Herman. 1998. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. International Journal of Clinical Pharmacology and Therapeutics 36: 345–349.PubMedGoogle Scholar
  2. 2.
    Keech, A., R.J. Simes, P. Barter, J. Best, R. Scott, M.R. Taskinen, P. Forder, A. Pillai, T. Davis, P. Glasziou, P. Drury, Y.A. Kesaniemi, D. Sullivan, D. Hunt, P. Colman, M. d’Emden, M. Whiting, C. Ehnholm, and M. Laakso. 2005. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet 366: 1849–1861.PubMedCrossRefGoogle Scholar
  3. 3.
    Fruchart, J.C., P. Duriez, and B. Staels. 1999. Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Current Opinion in Lipidology 10: 245–257.PubMedCrossRefGoogle Scholar
  4. 4.
    Duez, H., Y.S. Chao, M. Hernandez, G. Torpier, P. Poulain, S. Mundt, Z. Mallat, E. Teissier, C.A. Burton, A. Tedgui, J.C. Fruchart, C. Fievet, S.D. Wright, and B. Staels. 2002. Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice. Journal of Biological Chemistry 277: 48051–48057.PubMedCrossRefGoogle Scholar
  5. 5.
    Lin, R., J.T. Liu, W.J. Gan, W.R. Wang, C.J. Han, and Z.Y. Fang. 2006. Fenofibrate inhibits tumor necrosis factor-alpha-induced expression of CD40 and matrix metalloproteinase in human vascular endothelial cells. Journal of Southern Medical University 26: 1383–1387.PubMedGoogle Scholar
  6. 6.
    Rizvi, M., D. Pathak, J.E. Freedman, and S. Chakrabarti. 2008. CD40-CD40 ligand interactions in oxidative stress, inflammation and vascular disease. Trends in Molecular Medicine 14: 530–538.PubMedCrossRefGoogle Scholar
  7. 7.
    Haigis, M.C., and L.P. Guarente. 2006. Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes & Development 20: 2913–2921.CrossRefGoogle Scholar
  8. 8.
    Stein, S., and C.M. Matter. 2011. Protective roles of SIRT1 in atherosclerosis. Cell Cycle 10: 640–647.PubMedCrossRefGoogle Scholar
  9. 9.
    Csiszar, A., N. Labinskyy, A. Podlutsky, P.M. Kaminski, M.S. Wolin, C.H. Zhang, P. Mukhopadhyay, P. Pacher, F.R. Hu, R. de Cabo, P. Ballabh, and Z. Ungvari. 2008. Vasoprotective effects of resveratrol and SIRT1: Attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. American Journal of Physiology-Heart and Circulatory Physiology 294: H2721–H2735.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Csiszar, A., N. Labinskyy, R. Jimenez, J.T. Pinto, P. Ballabh, G. Losonczy, K.J. Pearson, R. de Cabo, and Z. Ungvari. 2009. Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: Role of circulating factors and SIRT1. Mechanisms of Ageing and Development 130: 518–527.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Stein, S., N. Schafer, A. Breitenstein, C. Besler, S. Winnik, C. Lohmann, K. Heinrich, C.E. Brokopp, C. Handschin, U. Landmesser, F.C. Tanner, T.F. Luscher, and C.M. Matter. 2010. SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/-mice. Aging (Albany NY) 2: 353–360.Google Scholar
  12. 12.
    Salminen, A., A. Kauppinen, T. Suuronen, and K. Kaarniranta. 2008. Sirt1 longevity factor suppresses nf-kappa b-driven immune responses: Regulation of aging via nf-kappa b acetylation? Bioessays 30: 939–942.PubMedCrossRefGoogle Scholar
  13. 13.
    Lin, R., J.T. Liu, N. Peng, G.D. Yang, W.J. Gan, and W.R. Wang. 2005. Lovastatin reduces nuclear factor kappa b activation induced by C-reactive protein in human vascular endothelial cells. Biological & Pharmaceutical Bulletin 28: 1630–1634.CrossRefGoogle Scholar
  14. 14.
    Grozinger, C.M., E.D. Chao, H.E. Blackwell, D. Moazed, and S.L. Schreiber. 2001. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. Journal of Biological Chemistry 276: 38837–38843.PubMedCrossRefGoogle Scholar
  15. 15.
    Bitterman, K.J., R.M. Andersonm, H.Y. Cohen, M. Latorre-Esteves, and D.A. Sinclair. 2002. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. Journal of Biological Chemistry 277: 45099–45107.PubMedCrossRefGoogle Scholar
  16. 16.
    Yang, L.N., J.Y. Zhang, C.F. Yan, J. Zhou, R. Lin, Q.Q. Lin, W.R. Wang, K.F. Zhang, G.D. Yang, X.L. Bian, and A.G. Zeng. 2012. SIRT1 regulates CD40 expression induced by TNF-α via NF-κB pathway in endothelial cells. Cellular Physiology and Biochemistry 30: 1287–1298.PubMedCrossRefGoogle Scholar
  17. 17.
    Xu, H.E., T.B. Stanley, V.G. Montana, M.H. Lambert, B.G. Shearer, J.E. Cobb, D.D. McKee, C.M. Galardi, K.D. Plunket, R.T. Nolte, D.J. Parks, J.T. Moore, S.A. Kliewer, T.M. Willson, and J.B. Stimmel. 2002. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPAR alpha. Nature 415: 813–817.PubMedCrossRefGoogle Scholar
  18. 18.
    Sung, B., S. Park, B.P. Yu, and H.Y. Chung. 2004. Modulation of PPAR in aging, inflammation, and calorie restriction. Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59: 997–1006.CrossRefGoogle Scholar
  19. 19.
    Barroso, E., E. Eyre, X. Palomer, and M. Vazquez-Carrera. 2011. The peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) agonist GW501516 prevents TNF-alpha-induced NF-kappa B activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1. Biochemical Pharmacology 81: 534–543.PubMedCrossRefGoogle Scholar
  20. 20.
    Xue, B.Z., Z.G. Yang, X.F. Wang, and H. Shi. 2012. Omega-3 Polyunsaturated Fatty Acids Antagonize Macrophage Inflammation via Activation of AMPK/SIRT1 Pathway. PLoS ONE 7: 1–6.Google Scholar
  21. 21.
    Lin, R., J.T. Liu, W.J. Gan, and G.D. Yang. 2004. C-reactive protein-induced expression of CD40-CD40L and the effect of lovastatin and fenofibrate on it in human vascular endothelial cells. Biological & Pharmaceutical Bulletin 27: 1537–1543.CrossRefGoogle Scholar
  22. 22.
    Fang, Z.Y., R. Lin, B.X. Yuan, Y. Liu, and H. Zhang. 2007. Tanshinone IIA inhibits atherosclerotic plaque formation by down-regulating MMP-2 and MMP-9 expression in rabbits fed a high-fat diet. Life Sciences 81: 1339–1345.PubMedCrossRefGoogle Scholar
  23. 23.
    Gocmen, A.Y., D. Burgucu, and S. Gumuslu. 2011. Effect of resveratrol on platelet activation in hypercholesterolemic rats: CD40-CD40L system as a potentialtarget. Applied Physiology Nutrition and Metabolism-Physiologie Appliquee Nutrition et Metabolisme 36: 323–330.CrossRefGoogle Scholar
  24. 24.
    Cheng, H.L., R. Mostoslavsky, S. Saito, J.P. Manis, Y.S. Gu, P. Patel, R. Bronson, E. Appella, F.W. Alt, and K.F. Chua. 2003. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proceedings of the National Academy of Sciences of the United States of the United States of America 100: 10794–10799.CrossRefGoogle Scholar
  25. 25.
    Yeung, F., J.E. Hoberg, C.S. Ramsey, M.D. Keller, D.R. Jones, R.A. Frye, and M.W. Mayo. 2004. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO Journal 23: 2369–2380.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Marx, N., G.K. Sukhova, T. Collins, P. Libby, and J. Plutzky. 1999. PPAR alpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 99: 3125–3131.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Yang, T.L., M.F. Chen, B.L. Luo, Q.Y. Xie, J.L. Jiang, and Y.J. Li. 2005. Fenofibrate decreases asymmetric dimethylarginine level in cultured endothelial cells by inhibiting NF-κB activity. Naunyn-Schmiedeberg’s Archives of Pharmacology 371: 401–407.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang, Y.F., Y. Xiao, J. Yang, Y.N. Wu, X.L. Wang, R. Zou, M. Zhang, Q.Y. Liu, N. Guo, X.Q. Luo, X.Q. Dong, and X.Q. Yu. 2009. Rosiglitazone down-regulates lipopolysaccharide-induced expression of CD40 and intercellular adhesion molecule 1 in rat peritoneal mesothelial cells through a NF-kappaB dependent mechanism. Chinese Journal of Nephrology 25: 430–436.Google Scholar
  29. 29.
    Karin, M., and Y. Ben-Neriah. 2000. Phosphorylation meets ubiquitination: The control of NF-kappa B activity. Annual Review of Immunology 18: 621.PubMedCrossRefGoogle Scholar
  30. 30.
    Tak, P.P., and G.S. Firestein. 2001. NF-kappaB: A key role in inflammatory diseases. Journal of Clinical Investigation 107: 7–11.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Chen, L.F., Y.J. Mu, and W.C. Greene. 2002. Acetylation of ReIA at discrete sites regulates distinct nuclear functions of NF-kappa B. EMBO Journal 21: 6539–6548.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Kiernan, R., V. Bres, R.W.M. Ng, M.P. Coudart, S. El Messaoudi, C. Sardet, D.Y. Jin, S. Emiliani, and M. Benkirane. 2003. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. Journal of Biological Chemistry 278: 2758–2766.PubMedCrossRefGoogle Scholar
  33. 33.
    Viatour, P., S. Legrand-Poels, C. van Lint, M. Warnier, M.P. Merville, J. Gielen, J. Piette, V. Bours, and A. Chariot. 2003. Cytoplasmic I kappa B alpha increases NF-kappa B-independent transcription through binding to histone deacetylase (HDAC)1 and HDAC3. Journal of Biological Chemistry 278: 46541–46548.PubMedCrossRefGoogle Scholar
  34. 34.
    Seong, A.R., J.Y. Yoo, K. Choi, M.H. Lee, Y.H. Lee, J. Lee, W. Jun, S. Kim, and H.G. Yoon. 2011. Delphinidin, a specific inhibitor of histone acetyltransferase, suppresses inflammatory signaling via prevention of NF-kappa B acetylation in fibroblast-like synoviocyte MH7A cells. Biochemical and Biophysical Research Communications 410: 581–586.PubMedCrossRefGoogle Scholar
  35. 35.
    Lei, M., J.G. Wang, D.M. Xiao, M. Fan, D.P. Wang, J.Y. Xiong, Y. Chen, Y. Ding, and S.L. Liu. 2012. Resveratrol inhibits interleukin 1 beta-mediated inducible nitric oxide synthase expression in articular chondrocytes by activating SIRT1 and thereby suppressing nuclear factor-kappa B activity. European Journal of Pharmacology 674: 73–79.PubMedCrossRefGoogle Scholar
  36. 36.
    Okopien, B., R. Krysiak, and Z.S. Herman. 2006. Effects of short-term fenofibrate treatment on circulating markers of inflammation and hemostasis in patients with impaired glucose tolerance. Journal of Clinical Endocrinology & Metabolism 91: 1770–1778.CrossRefGoogle Scholar
  37. 37.
    Delerive, P., J. Fruchart, and B. Staels. 2001. Peroxisome proliferator-activated receptors in inflammation control. Journal of Endocrinology 169: 453–459.PubMedCrossRefGoogle Scholar
  38. 38.
    Fokko, Z.A., and J. Plutzky. 2007. PPAR alpha in atherosclerosis and inflammation. Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids 1771: 972–982.CrossRefGoogle Scholar
  39. 39.
    Tomizawa, A., Y. Hattori, T. Inoue, S. Hattori, and K. Kasai. 2011. Fenofibrate suppresses microvascular inflammation and apoptosis through adenosine monophosphate-activated protein kinase activation. Metabolism-Clinical and Experimental 60: 513–522.PubMedCrossRefGoogle Scholar
  40. 40.
    Planavila, A., R. Iglesias, M. Giralt, and F. Villarroya. 2011. Sirt1 acts in association with PPAR alpha to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. Cardiovascular Research 90: 276–284.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Weirong Wang
    • 1
  • Ling Bai
    • 2
  • Hu Qiao
    • 3
  • Yanxiang Li
    • 1
  • Lina Yang
    • 1
  • Jiye Zhang
    • 1
  • Rong Lin
    • 1
  • Feng Ren
    • 1
  • Jianfeng Zhang
    • 1
  • Meixi Ji
    • 1
  1. 1.Department of Pharmacology, Cardiovascular Research Center, School of MedicineXi’an Jiaotong UniversityXi’anChina
  2. 2.The Cardiovascular Department of The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
  3. 3.Department of Physiology and Pathophysiology, School of MedicineXi’an Jiaotong UniversityXi’anChina

Personalised recommendations