Skip to main content
SpringerLink
Log in

Role of PPARs in Inflammation, Atherosclerosis, and Thrombosis

  • Chapter
Peroxisome Proliferator Activated Receptors: From Basic Science to Clinical Applications

Part of the book series: Medical Science Symposia Series ((MSSS,volume 18))

Abstract

Peroxisome proliferator-activated receptors (PPARs) are a subfamily of nuclear receptors comprising 3 isotypes, PPARα, β/δ, and γ, which control a variety of cellular functions such as lipid and lipoprotein metabolism, fatty acid oxidation, glucose metabolism, adipogenesis, and cellular differentiation. Moreover, emerging data suggest that, besides their role in regulating metabolic risk factors for cardiovascular diseases, PPARs are involved in the control of vascular inflammation and thrombogenicity related to atherosclerosis. This review will focus on recent developments on the role of PPARα and γ in this field.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): Nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000;49(10):497–505.

    Article  PubMed  CAS  Google Scholar 

  2. Ricote M, Huang J, Fajas L, et al. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA 1998;95(13):7614–19.

    Article  PubMed  CAS  Google Scholar 

  3. Marx N, Sukhova G, Murphy C, Libby P, Plutzky J. Macrophages in human atheroma contain PPARgamma: Differentiation-dependent peroxisomal proliferator-activated receptor gamma (PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am J Pathol 1998; 153(1): 17–23.

    Article  PubMed  CAS  Google Scholar 

  4. Greene ME, Blumberg B, McBride OW, et al. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: Expression in hematopoietic cells and chromosomal mapping. Gene Expr 1995;4(4–5):281–99.

    PubMed  CAS  Google Scholar 

  5. Padilla J, Kaur K, Harris SG, Phipps RP. PPAR-gamma-mediated regulation of normal and malignant B lineage cells. Ann NY Acad Sci 2000;905:97–109.

    Article  PubMed  CAS  Google Scholar 

  6. Yang XY, Wang LH, Chen T, et al. Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. J Biol Chem 2000;275(7):4541–44.

    Article  PubMed  CAS  Google Scholar 

  7. Marx N, Sukhova GK, Collins T, Libby P, Plutzky J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 1999;99(24):3125–31.

    Article  PubMed  CAS  Google Scholar 

  8. Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J. PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vase Biol 1999;19(3):546–51.

    Article  CAS  Google Scholar 

  9. Inoue I, Shino K, Noji S, Awata T, Katayama S. Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. Biochem Biophys Res Commun 1998;246(2):370–74.

    Article  PubMed  CAS  Google Scholar 

  10. Marx N, Schonbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 1998;83(11): 1097–103.

    Article  PubMed  CAS  Google Scholar 

  11. Faveeuw C, Fougeray S, Angeli V, et al. Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett 2000;486(3):261–66.

    Article  PubMed  CAS  Google Scholar 

  12. Chinetti G, Gbaguidi FG, Griglio S, et al. CLA-l/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation 2000;101(20):2411–17.

    Article  PubMed  CAS  Google Scholar 

  13. Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 1997;94(9):4312–17.

    Article  PubMed  CAS  Google Scholar 

  14. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 1997;94(9):4318–23.

    Article  PubMed  CAS  Google Scholar 

  15. Huang JT, Welch JS, Ricote M, et al. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 1999;400(6742):378–82.

    Article  PubMed  CAS  Google Scholar 

  16. Delerive P, De Bosscher K, Besnard S, et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 1999;274(45):32048–54.

    Article  PubMed  CAS  Google Scholar 

  17. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998;391 (6662): 79–82.

    Article  PubMed  CAS  Google Scholar 

  18. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 1998;393(6687):790–93.

    Article  PubMed  CAS  Google Scholar 

  19. Chung SW, Kang BY, Kim SH, et al. Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. J Biol Chem 2000;275(42):32681–87.

    Article  PubMed  CAS  Google Scholar 

  20. Delerive P, Gervois P, Fruchart JC, Staels B. Induction of ikappa balpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem 2000;275(47):36703–7.

    Article  PubMed  CAS  Google Scholar 

  21. Lusis AJ. Atherosclerosis. Nature 2000;407(6801):233–41.

    Article  PubMed  CAS  Google Scholar 

  22. Frick MH, Syvanne M, Nieminen MS, et al. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study. Circulation 1997;96(7):2137–43.

    Article  PubMed  CAS  Google Scholar 

  23. Ruotolo G, Ericsson CG, Tettamanti C, et al. Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). J Am Coll Cardiol 1998;32(6): 1648–56.

    Article  PubMed  CAS  Google Scholar 

  24. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 1996;347(9005):849–53.

    Article  PubMed  CAS  Google Scholar 

  25. Minamikawa J, Tanaka S, Yamauchi M, Inoue D, Koshiyama H. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 1998;83(5): 1818–20.

    Article  PubMed  CAS  Google Scholar 

  26. Chinetti G, Griglio S, Antonucci M, et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 1998;273(40):25573–80.

    Article  PubMed  CAS  Google Scholar 

  27. Moore KJ, Rosen ED, Fitzgerald ML, et al. The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat Med 2001;7(1):41–47.

    Article  PubMed  CAS  Google Scholar 

  28. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;391(6662):82–86.

    Article  PubMed  CAS  Google Scholar 

  29. Callejas NA, Castrillo A, Bosca L, Martin-Sanz P. Inhibition of prostaglandin synthesis up-regulates cyclooxygenase-2 induced by lipopolysaccharide and peroxisomal proliferators. J Pharmacol Exp Ther 1999;288(3): 1235–41.

    PubMed  CAS  Google Scholar 

  30. Rossi A, Kapahi P, Natoli G, et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature 2000;403(6765): 103–8.

    Article  PubMed  CAS  Google Scholar 

  31. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001;7(1):48–52.

    Article  PubMed  CAS  Google Scholar 

  32. Chinetti G, Lestavel S, Bocher V, et al. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 2001;7(1):53–58.

    Article  PubMed  CAS  Google Scholar 

  33. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998;93(2):241–52.

    Article  PubMed  CAS  Google Scholar 

  34. Febbraio M, Podrez EA, Smith JD, et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest 2000;105(8):1049–56.

    Article  PubMed  CAS  Google Scholar 

  35. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998;93(2):229–40.

    Article  PubMed  CAS  Google Scholar 

  36. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000;106(4):523–31.

    Article  PubMed  CAS  Google Scholar 

  37. Han KH, Chang MK, Boullier A, et al. Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor gamma. J Clin Invest 2000;106(6):793–802.

    Article  PubMed  CAS  Google Scholar 

  38. Shu H, Wong B, Zhou G, et al. Activation of PPARalpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells. Biochem Biophys Res Commun 2000;267(1):345–49.

    Article  PubMed  CAS  Google Scholar 

  39. Neve B, Corseaux D, Chinetti G, et al. PPARα agonists inhibit tissue factor expression in human monocytes and macrophages. Circulation 2001; 103(2):207–12.

    Article  PubMed  CAS  Google Scholar 

  40. Marx N, Mackman N, Schönbeck U, et al. PPARa activators inhibit tissue factor expression and activity in human monocytes. Circulation 2001;103(2):213–19.

    Article  PubMed  CAS  Google Scholar 

  41. Murao K, Imachi H, Momoi A, et al. Thiazolidinedione inhibits the production of monocyte chemoattractant protein-1 in cytokine-treated human vascular endothelial cells. FEBS Lett 1999;454(1–2):27–30.

    Article  PubMed  CAS  Google Scholar 

  42. Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation 2000;101(3):235–38.

    Article  PubMed  CAS  Google Scholar 

  43. Jackson SM, Parhami F, Xi XP, et al. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler Thromb Vase Biol 1999;19(9):2094–104.

    Article  CAS  Google Scholar 

  44. Marx N, Mach F, Sauty A, et al. Peroxisome proliferator-activated receptor-gamma activators inhibit IFN- gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells. J Immunol 2000;164(12):6503–8.

    PubMed  CAS  Google Scholar 

  45. Delerive P, Martin-Nizard F, Chinetti G, et al. Peroxisome proliferator-activated receptor activators inhibit thrombin- induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res 1999;85(5):394–402.

    Article  PubMed  CAS  Google Scholar 

  46. Law RE, Goetze S, Xi XP, et al. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation 2000; 101(11): 1311–18.

    Article  PubMed  CAS  Google Scholar 

  47. Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol 2000;164(3): 1364–71.

    PubMed  CAS  Google Scholar 

  48. Sugiyama H, Nonaka T, Kishimoto T, Komoriya K, Tsuji K, Nakahata T. Peroxisome proliferator-activated receptors are expressed in mouse bone marrow-derived mast cells. FEBS Lett 2000;467(2–3):259–62.

    Article  PubMed  CAS  Google Scholar 

  49. Li H, Reddick RL, Maeda N. Lack of apoA-I is not associated with increased susceptibility to atherosclerosis in mice. Arterioscler Thromb 1993;13(12).1814–21.

    Article  PubMed  CAS  Google Scholar 

  50. Gosset P, Charbonnier A-S, Delerive P, et al. PPARγ activators affect the maturation of human dendritic cells. Eur J Immunol 2001; submitted.

    Google Scholar 

  51. Tanaka T, Itoh H, Doi K, et al. Down regulation of peroxisome proliferator-activated receptorgamma expression by inflammatory cytokines and its reversal by thiazolidinediones. Diabetologia 1999;42(6):702–10.

    Article  PubMed  CAS  Google Scholar 

  52. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 1996;384(6604):39–43.

    Article  PubMed  CAS  Google Scholar 

  53. Poynter ME, Daynes RA. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 1998;273(49):32833–41.

    Article  PubMed  CAS  Google Scholar 

  54. Okuno A, Tamemoto H, Tobe K, et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998;101(6):1354–61.

    Article  PubMed  CAS  Google Scholar 

  55. Madej A, Okopien B, Kowalski J, et al. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. Int J Clin Pharmacol Ther 1998;36(6):345–49.

    PubMed  CAS  Google Scholar 

  56. Kockx M, Gervois PP, Poulain P, et al. Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha. Blood 1999; 93(9):2991–98.

    PubMed  CAS  Google Scholar 

  57. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341(6):410–18.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Antoine Pilon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hélène Duez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Charles Fruchart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bart Staels
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Faculté des Sciences Pharmaceutiques et Biologiques, Inserm U 545, Dept. Atherosclerose, Institut Pasteur de Lille, Université de Lille II, Lille, France

    J.-C. Fruchart

  2. Weill Medical College of Cornell University, New York, New York, USA

    A. M. Gotto Jr.

  3. Department of Pharmacological Sciences, University of Milan, Milan, Italy

    R. Paoletti  & A. L. Catapano  & 

  4. Department of Atherosclerosis, Pasteur Institute, Inserm U 545, University of Lille II, Lille, France

    B. Staels

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Pilon, A., Duez, H., Fruchart, JC., Staels, B. (2002). Role of PPARs in Inflammation, Atherosclerosis, and Thrombosis. In: Fruchart, JC., Gotto, A.M., Paoletti, R., Staels, B., Catapano, A.L. (eds) Peroxisome Proliferator Activated Receptors: From Basic Science to Clinical Applications. Medical Science Symposia Series, vol 18. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1171-7_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-1171-7_5

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5427-7

  • Online ISBN: 978-1-4615-1171-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation