Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2001 Feb 15;354(Pt 1):225–232. doi: 10.1042/0264-6021:3540225

Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor alpha down-regulate platelet-activating-factor receptor expression in human macrophages.

D Hourton 1, P Delerive 1, J Stankova 1, B Staels 1, M J Chapman 1, E Ninio 1
PMCID: PMC1221647  PMID: 11171098

Abstract

Regulation of the expression of platelet-activating factor (PAF) receptor by atherogenic lipoproteins might contribute to atherogenesis. We show that progressive oxidation of low-density lipoprotein (LDL) gradually inhibits PAF receptor expression on the macrophage cell surface. We tested the effect of oxidized LDL (oxLDL) on PAF receptor expression in human monocytes that do not contain peroxisome-proliferator-activated receptor gamma (PPARgamma), a nuclear receptor activated by oxLDL. OxLDL decreased by 50% (P < or = 0.001) and by 29% (P < or = 0.05) the binding of PAF and the expression of PAF receptor mRNA respectively. Next we demonstrated that progressive oxidation of LDLs significantly activated PPARalpha-dependent transcription in transfected mouse aortic endothelial cells. Finally we demonstrated, in mature macrophages, that fenofibrate (20 microM), a specific PPARalpha agonist, but not the specific PPARgamma agonist BRL49653 (20 nM), significantly decreased both PAF binding and PAF receptor mRNA expression, by 65% and 40% (P < or = 0.001) respectively. Additionally, another PPARalpha agonist, Wy14,643, decreased PAF receptor promoter activity by 70% (P < or = 0.05) in transfected THP-1 cells, suggesting the involvement of the proximal promoter region (-980 to -500) containing a series of four nuclear factor (NF)-kappaB motifs. Thus PPARalpha might be involved in the down-regulation of PAF receptor gene expression by oxLDLs in human monocytes/macrophages. The oxidation of one or more lipid components of LDLs might result in the formation of natural activators of PPARalpha. It is hypothesized that such activators might modulate inflammation and apoptosis upon atherogenesis by decreasing the expression of PAF receptor.

Full Text

The Full Text of this article is available as a PDF (151.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ali H., Richardson R. M., Tomhave E. D., DuBose R. A., Haribabu B., Snyderman R. Regulation of stably transfected platelet activating factor receptor in RBL-2H3 cells. Role of multiple G proteins and receptor phosphorylation. J Biol Chem. 1994 Oct 7;269(40):24557–24563. [PubMed] [Google Scholar]
  2. Berliner J. A., Navab M., Fogelman A. M., Frank J. S., Demer L. L., Edwards P. A., Watson A. D., Lusis A. J. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995 May 1;91(9):2488–2496. doi: 10.1161/01.cir.91.9.2488. [DOI] [PubMed] [Google Scholar]
  3. Brochériou I., Stengel D., Mattsson-Hultén L., Stankova J., Rola-Pleszczynski M., Koskas F., Wiklund O., Le Charpentier Y., Ninio E. Expression of platelet-activating factor receptor in human carotid atherosclerotic plaques: relevance to progression of atherosclerosis. Circulation. 2000 Nov 21;102(21):2569–2575. doi: 10.1161/01.cir.102.21.2569. [DOI] [PubMed] [Google Scholar]
  4. Chao W., Olson M. S. Platelet-activating factor: receptors and signal transduction. Biochem J. 1993 Jun 15;292(Pt 3):617–629. doi: 10.1042/bj2920617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chaqour B., Howard P. S., Richards C. F., Macarak E. J. Mechanical stretch induces platelet-activating factor receptor gene expression through the NF-kappaB transcription factor. J Mol Cell Cardiol. 1999 Jul;31(7):1345–1355. doi: 10.1006/jmcc.1999.0967. [DOI] [PubMed] [Google Scholar]
  6. Chinetti G., Griglio S., Antonucci M., Torra I. P., Delerive P., Majd Z., Fruchart J. C., Chapman J., Najib J., Staels B. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem. 1998 Oct 2;273(40):25573–25580. doi: 10.1074/jbc.273.40.25573. [DOI] [PubMed] [Google Scholar]
  7. 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. 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 Nov 5;274(45):32048–32054. doi: 10.1074/jbc.274.45.32048. [DOI] [PubMed] [Google Scholar]
  8. Delerive P., Furman C., Teissier E., Fruchart J., Duriez P., Staels B. Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner. FEBS Lett. 2000 Apr 7;471(1):34–38. doi: 10.1016/s0014-5793(00)01364-8. [DOI] [PubMed] [Google Scholar]
  9. Dentan C., Lesnik P., Chapman M. J., Ninio E. Phagocytic activation induces formation of platelet-activating factor in human monocyte-derived macrophages and in macrophage-derived foam cells. Relevance to the inflammatory reaction in atherogenesis. Eur J Biochem. 1996 Feb 15;236(1):48–55. doi: 10.1111/j.1432-1033.1996.00048.x. [DOI] [PubMed] [Google Scholar]
  10. Devchand P. R., Keller H., Peters J. M., Vazquez M., Gonzalez F. J., Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 1996 Nov 7;384(6604):39–43. doi: 10.1038/384039a0. [DOI] [PubMed] [Google Scholar]
  11. Esterbauer H., Dieber-Rotheneder M., Waeg G., Striegl G., Jürgens G. Biochemical, structural, and functional properties of oxidized low-density lipoprotein. Chem Res Toxicol. 1990 Mar-Apr;3(2):77–92. doi: 10.1021/tx00014a001. [DOI] [PubMed] [Google Scholar]
  12. Forman B. M., Chen J., Evans R. M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312–4317. doi: 10.1073/pnas.94.9.4312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Forman B. M., Tontonoz P., Chen J., Brun R. P., Spiegelman B. M., Evans R. M. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995 Dec 1;83(5):803–812. doi: 10.1016/0092-8674(95)90193-0. [DOI] [PubMed] [Google Scholar]
  14. Frankenberger M., Pforte A., Sternsdorf T., Passlick B., Baeuerle P. A., Ziegler-Heitbrock H. W. Constitutive nuclear NF-kappa B in cells of the monocyte lineage. Biochem J. 1994 Nov 15;304(Pt 1):87–94. doi: 10.1042/bj3040087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Frick M. H., Syvänne M., Nieminen M. S., Kauma H., Majahalme S., Virtanen V., Kesäniemi Y. A., Pasternack A., Taskinen M. R. 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 Group. Circulation. 1997 Oct 7;96(7):2137–2143. doi: 10.1161/01.cir.96.7.2137. [DOI] [PubMed] [Google Scholar]
  16. Geng Y., Kodama T., Hansson G. K. Differential expression of scavenger receptor isoforms during monocyte-macrophage differentiation and foam cell formation. Arterioscler Thromb. 1994 May;14(5):798–806. doi: 10.1161/01.atv.14.5.798. [DOI] [PubMed] [Google Scholar]
  17. Gieseg S. P., Esterbauer H. Low density lipoprotein is saturable by pro-oxidant copper. FEBS Lett. 1994 May 2;343(3):188–194. doi: 10.1016/0014-5793(94)80553-9. [DOI] [PubMed] [Google Scholar]
  18. Harland W. A., Gilbert J. D., Steel G., Brooks C. J. Lipids of human atheroma. 5. The occurrence of a new group of polar sterol esters in various stages of human atherosclerosis. Atherosclerosis. 1971 Mar-Apr;13(2):239–246. doi: 10.1016/0021-9150(71)90026-8. [DOI] [PubMed] [Google Scholar]
  19. Honda Z., Nakamura M., Miki I., Minami M., Watanabe T., Seyama Y., Okado H., Toh H., Ito K., Miyamoto T. Cloning by functional expression of platelet-activating factor receptor from guinea-pig lung. Nature. 1991 Jan 24;349(6307):342–346. doi: 10.1038/349342a0. [DOI] [PubMed] [Google Scholar]
  20. Honda Z., Takano T., Gotoh Y., Nishida E., Ito K., Shimizu T. Transfected platelet-activating factor receptor activates mitogen-activated protein (MAP) kinase and MAP kinase kinase in Chinese hamster ovary cells. J Biol Chem. 1994 Jan 21;269(3):2307–2315. [PubMed] [Google Scholar]
  21. Jiang C., Ting A. T., Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998 Jan 1;391(6662):82–86. doi: 10.1038/34184. [DOI] [PubMed] [Google Scholar]
  22. Kliewer S. A., Sundseth S. S., Jones S. A., Brown P. J., Wisely G. B., Koble C. S., Devchand P., Wahli W., Willson T. M., Lenhard J. M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4318–4323. doi: 10.1073/pnas.94.9.4318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kliewer S. A., Umesono K., Noonan D. J., Heyman R. A., Evans R. M. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature. 1992 Aug 27;358(6389):771–774. doi: 10.1038/358771a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lehmann J. M., Moore L. B., Smith-Oliver T. A., Wilkison W. O., Willson T. M., Kliewer S. A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995 Jun 2;270(22):12953–12956. doi: 10.1074/jbc.270.22.12953. [DOI] [PubMed] [Google Scholar]
  25. Lehr H. A., Seemüller J., Hübner C., Menger M. D., Messmer K. Oxidized LDL-induced leukocyte/endothelium interaction in vivo involves the receptor for platelet-activating factor. Arterioscler Thromb. 1993 Jul;13(7):1013–1018. doi: 10.1161/01.atv.13.7.1013. [DOI] [PubMed] [Google Scholar]
  26. Lenz M. L., Hughes H., Mitchell J. R., Via D. P., Guyton J. R., Taylor A. A., Gotto A. M., Jr, Smith C. V. Lipid hydroperoxy and hydroxy derivatives in copper-catalyzed oxidation of low density lipoprotein. J Lipid Res. 1990 Jun;31(6):1043–1050. [PubMed] [Google Scholar]
  27. Moya-Camarena S. Y., Vanden Heuvel J. P., Blanchard S. G., Leesnitzer L. A., Belury M. A. Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARalpha. J Lipid Res. 1999 Aug;40(8):1426–1433. [PubMed] [Google Scholar]
  28. Mueller H. W., Haught C. A., McNatt J. M., Cui K., Gaskell S. J., Johnston D. A., Willerson J. T. Measurement of platelet-activating factor in a canine model of coronary thrombosis and in endarterectomy samples from patients with advanced coronary artery disease. Circ Res. 1995 Jul;77(1):54–63. doi: 10.1161/01.res.77.1.54. [DOI] [PubMed] [Google Scholar]
  29. Mutoh H., Bito H., Minami M., Nakamura M., Honda Z., Izumi T., Nakata R., Kurachi Y., Terano A., Shimizu T. Two different promoters direct expression of two distinct forms of mRNAs of human platelet-activating factor receptor. FEBS Lett. 1993 May 10;322(2):129–134. doi: 10.1016/0014-5793(93)81552-b. [DOI] [PubMed] [Google Scholar]
  30. Nagy L., Tontonoz P., Alvarez J. G., Chen H., Evans R. M. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998 Apr 17;93(2):229–240. doi: 10.1016/s0092-8674(00)81574-3. [DOI] [PubMed] [Google Scholar]
  31. Nakamura M., Honda Z., Izumi T., Sakanaka C., Mutoh H., Minami M., Bito H., Seyama Y., Matsumoto T., Noma M. Molecular cloning and expression of platelet-activating factor receptor from human leukocytes. J Biol Chem. 1991 Oct 25;266(30):20400–20405. [PubMed] [Google Scholar]
  32. Pang J. H., Hung R. Y., Wu C. J., Fang Y. Y., Chau L. Y. Functional characterization of the promoter region of the platelet-activating factor receptor gene. Identification of an initiator element essential for gene expression in myeloid cells. J Biol Chem. 1995 Jun 9;270(23):14123–14129. doi: 10.1074/jbc.270.23.14123. [DOI] [PubMed] [Google Scholar]
  33. Ricote M., Li A. C., Willson T. M., Kelly C. J., Glass C. K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998 Jan 1;391(6662):79–82. doi: 10.1038/34178. [DOI] [PubMed] [Google Scholar]
  34. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115–126. doi: 10.1056/NEJM199901143400207. [DOI] [PubMed] [Google Scholar]
  35. Rouis M., Nigon F., Chapman M. J. Platelet activating factor is a potent stimulant of the production of active oxygen species by human monocyte-derived macrophages. Biochem Biophys Res Commun. 1988 Nov 15;156(3):1293–1301. doi: 10.1016/s0006-291x(88)80773-3. [DOI] [PubMed] [Google Scholar]
  36. Rouis M., Nigon F., Lafuma C., Hornebeck W., Chapman M. J. Expression of elastase activity by human monocyte-macrophages is modulated by cellular cholesterol content, inflammatory mediators, and phorbol myristate acetate. Arteriosclerosis. 1990 Mar-Apr;10(2):246–255. doi: 10.1161/01.atv.10.2.246. [DOI] [PubMed] [Google Scholar]
  37. Schoonjans K., Martin G., Staels B., Auwerx J. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol. 1997 Jun;8(3):159–166. doi: 10.1097/00041433-199706000-00006. [DOI] [PubMed] [Google Scholar]
  38. Snyder F. Platelet-activating factor and its analogs: metabolic pathways and related intracellular processes. Biochim Biophys Acta. 1995 Feb 9;1254(3):231–249. doi: 10.1016/0005-2760(94)00192-2. [DOI] [PubMed] [Google Scholar]
  39. Staels B., Koenig W., Habib A., Merval R., Lebret M., Torra I. P., Delerive P., Fadel A., Chinetti G., Fruchart J. C. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature. 1998 Jun 25;393(6687):790–793. doi: 10.1038/31701. [DOI] [PubMed] [Google Scholar]
  40. Steinbrecher U. P. Receptors for oxidized low density lipoprotein. Biochim Biophys Acta. 1999 Jan 4;1436(3):279–298. doi: 10.1016/s0005-2760(98)00127-1. [DOI] [PubMed] [Google Scholar]
  41. Stengel D., Antonucci M., Arborati M., Hourton D., Griglio S., Chapman M. J., Ninio E. Expression of the PAF receptor in human monocyte-derived macrophages is downregulated by oxidized LDL: relevance to the inflammatory phase of atherogenesis. Arterioscler Thromb Vasc Biol. 1997 May;17(5):954–962. doi: 10.1161/01.atv.17.5.954. [DOI] [PubMed] [Google Scholar]
  42. Subbanagounder G., Leitinger N., Shih P. T., Faull K. F., Berliner J. A. Evidence that phospholipid oxidation products and/or platelet-activating factor play an important role in early atherogenesis : in vitro and In vivo inhibition by WEB 2086. Circ Res. 1999 Aug 20;85(4):311–318. doi: 10.1161/01.res.85.4.311. [DOI] [PubMed] [Google Scholar]
  43. Thieringer R., Fenyk-Melody J. E., Le Grand C. B., Shelton B. A., Detmers P. A., Somers E. P., Carbin L., Moller D. E., Wright S. D., Berger J. Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol. 2000 Jan 15;164(2):1046–1054. doi: 10.4049/jimmunol.164.2.1046. [DOI] [PubMed] [Google Scholar]
  44. Thivierge M., Alami N., Müller E., de Brum-Fernandes A. J., Rola-Pleszczynski M. Transcriptional modulation of platelet-activating factor receptor gene expression by cyclic AMP. J Biol Chem. 1993 Aug 15;268(23):17457–17462. [PubMed] [Google Scholar]
  45. Thomas C. E., Jackson R. L. Lipid hydroperoxide involvement in copper-dependent and independent oxidation of low density lipoproteins. J Pharmacol Exp Ther. 1991 Mar;256(3):1182–1188. [PubMed] [Google Scholar]
  46. Toledano B. J., Bastien Y., Noya F., Baruchel S., Mazer B. Platelet-activating factor abrogates apoptosis induced by cross-linking of the surface IgM receptor in a human B lymphoblastoid cell line. J Immunol. 1997 Apr 15;158(8):3705–3715. [PubMed] [Google Scholar]
  47. Tontonoz P., Nagy L., Alvarez J. G., Thomazy V. A., Evans R. M. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 1998 Apr 17;93(2):241–252. doi: 10.1016/s0092-8674(00)81575-5. [DOI] [PubMed] [Google Scholar]
  48. Tsoukatos D. C., Arborati M., Liapikos T., Clay K. L., Murphy R. C., Chapman M. J., Ninio E. Copper-catalyzed oxidation mediates PAF formation in human LDL subspecies. Protective role of PAF:acetylhydrolase in dense LDL. Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3505–3512. doi: 10.1161/01.atv.17.12.3505. [DOI] [PubMed] [Google Scholar]
  49. Wallin B., Rosengren B., Shertzer H. G., Camejo G. Lipoprotein oxidation and measurement of thiobarbituric acid reacting substances formation in a single microtiter plate: its use for evaluation of antioxidants. Anal Biochem. 1993 Jan;208(1):10–15. doi: 10.1006/abio.1993.1002. [DOI] [PubMed] [Google Scholar]
  50. Weyrich A. S., McIntyre T. M., McEver R. P., Prescott S. M., Zimmerman G. A. Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. J Clin Invest. 1995 May;95(5):2297–2303. doi: 10.1172/JCI117921. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES