Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2003 Dec 1;376(Pt 2):351–360. doi: 10.1042/BJ20030098

Oxysterol and 9-cis-retinoic acid stimulate the group IIA secretory phospholipase A2 gene in rat smooth-muscle cells.

Valérie Antonio 1, Brigitte Janvier 1, Arthur Brouillet 1, Marise Andreani 1, Michel Raymondjean 1
PMCID: PMC1223770  PMID: 12882648

Abstract

The inflammation that occurs during rheumatoid arthritis or atherosclerosis is characterized by the release of large amounts of sPLA(2) (group IIA secretory phospholipase A(2)). We have shown previously that the sPLA(2) promoter in SMC (smooth-muscle cells) is activated by interleukin-1beta and cAMP-signalling pathways, through the interplay of multiple transcription factors [Antonio, Brouillet, Janvier, Monne, Bereziat, Andreani, and Raymondjean (2002) Biochem. J. 368, 415-424]. In the present study, we have investigated the regulation of sPLA(2) gene expression in rat aortic SMCs by oxysterols. We found that oxysterol ligands that bind to the LXR (liver X receptor), including 25-HC (25-hydroxycholesterol) and 22( R )-HC, cause the accumulation of sPLA(2) mRNA and an increased enzyme activity. Transient transfection experiments demonstrated that the sPLA(2) promoter is synergistically activated by 22( R )-HC in combination with 9- cis -retinoic acid, a ligand for the LXR heterodimeric partner RXR (retinoid X receptor). Promoter activity was also increased in a sterol-responsive fashion when cells were co-transfected with LXRalpha/RXRalpha or LXRbeta/RXRalpha. Mutagenesis studies and gel mobility-shift assays revealed that LXR/RXR heterodimers regulate sPLA(2) transcription directly, by interacting with a degenerated LXRE (LXR response element) at position [-421/-406] of the sPLA(2) promoter. Chromatin immunoprecipitation revealed the in vivo occupancy of LXR on the sPLA(2) promoter. In addition, the orphan nuclear receptor LRH-1 (liver receptor homologue-1) potentiated the sterol-dependent regulation of the sPLA(2) promoter by binding to an identified promoter element (TCAAGGCTG). Finally, we have demonstrated that oxysterols act independent of interleukin-1beta and cAMP pathways to activate the sPLA(2) promoter. In the present study, we have identified a new pathway activating sPLA(2) gene expression in SMCs.

Full Text

The Full Text of this article is available as a PDF (289.1 KB).

Selected References

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

  1. Anthonsen M. W., Stengel D., Hourton D., Ninio E., Johansen B. Mildly oxidized LDL induces expression of group IIa secretory phospholipase A(2) in human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol. 2000 May;20(5):1276–1282. doi: 10.1161/01.atv.20.5.1276. [DOI] [PubMed] [Google Scholar]
  2. Antonio Valérie, Brouillet Arthur, Janvier Brigitte, Monne Claire, Bereziat Gilbert, Andreani Marise, Raymondjean Michel. Transcriptional regulation of the rat type IIA phospholipase A2 gene by cAMP and interleukin-1beta in vascular smooth muscle cells: interplay of the CCAAT/enhancer binding protein (C/EBP), nuclear factor-kappaB and Ets transcription factors. Biochem J. 2002 Dec 1;368(Pt 2):415–424. doi: 10.1042/BJ20020658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown A. J., Dean R. T., Jessup W. Free and esterified oxysterol: formation during copper-oxidation of low density lipoprotein and uptake by macrophages. J Lipid Res. 1996 Feb;37(2):320–335. [PubMed] [Google Scholar]
  4. Brown A. J., Jessup W. Oxysterols and atherosclerosis. Atherosclerosis. 1999 Jan;142(1):1–28. doi: 10.1016/s0021-9150(98)00196-8. [DOI] [PubMed] [Google Scholar]
  5. Chawla A., Boisvert W. A., Lee C. H., Laffitte B. A., Barak Y., Joseph S. B., Liao D., Nagy L., Edwards P. A., Curtiss L. K. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001 Jan;7(1):161–171. doi: 10.1016/s1097-2765(01)00164-2. [DOI] [PubMed] [Google Scholar]
  6. Chiang J. Y., Kimmel R., Stroup D. Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene. 2001 Jan 10;262(1-2):257–265. doi: 10.1016/s0378-1119(00)00518-7. [DOI] [PubMed] [Google Scholar]
  7. Costet P., Luo Y., Wang N., Tall A. R. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem. 2000 Sep 8;275(36):28240–28245. doi: 10.1074/jbc.M003337200. [DOI] [PubMed] [Google Scholar]
  8. Couturier C., Antonio V., Brouillet A., Béréziat G., Raymondjean M., Andréani M. Protein kinase A-dependent stimulation of rat type II secreted phospholipase A(2) gene transcription involves C/EBP-beta and -delta in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000 Dec;20(12):2559–2565. doi: 10.1161/01.atv.20.12.2559. [DOI] [PubMed] [Google Scholar]
  9. Davis Roger A., Miyake Jon H., Hui To Yuen, Spann Nathanael J. Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP. J Lipid Res. 2002 Apr;43(4):533–543. [PubMed] [Google Scholar]
  10. Forsberg E. C., Downs K. M., Bresnick E. H. Direct interaction of NF-E2 with hypersensitive site 2 of the beta-globin locus control region in living cells. Blood. 2000 Jul 1;96(1):334–339. [PubMed] [Google Scholar]
  11. Hurt-Camejo E., Camejo G., Peilot H., Oörni K., Kovanen P. Phospholipase A(2) in vascular disease. Circ Res. 2001 Aug 17;89(4):298–304. doi: 10.1161/hh1601.095598. [DOI] [PubMed] [Google Scholar]
  12. Hurt-Camejo E., Camejo G., Sartipy P. Phospholipase A2 and small, dense low-density lipoprotein. Curr Opin Lipidol. 2000 Oct;11(5):465–471. doi: 10.1097/00041433-200010000-00004. [DOI] [PubMed] [Google Scholar]
  13. Janowski B. A., Grogan M. J., Jones S. A., Wisely G. B., Kliewer S. A., Corey E. J., Mangelsdorf D. J. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):266–271. doi: 10.1073/pnas.96.1.266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jaross Werner, Eckey Rolf, Menschikowski Mario. Biological effects of secretory phospholipase A(2) group IIA on lipoproteins and in atherogenesis. Eur J Clin Invest. 2002 Jun;32(6):383–393. doi: 10.1046/j.1365-2362.2002.01000.x. [DOI] [PubMed] [Google Scholar]
  15. Joseph Sean B., Laffitte Bryan A., Patel Parthive H., Watson Michael A., Matsukuma Karen E., Walczak Robert, Collins Jon L., Osborne Timothy F., Tontonoz Peter. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem. 2002 Jan 14;277(13):11019–11025. doi: 10.1074/jbc.M111041200. [DOI] [PubMed] [Google Scholar]
  16. Joseph Sean B., McKilligin Elaine, Pei Liming, Watson Michael A., Collins Alan R., Laffitte Bryan A., Chen Mingyi, Noh Grace, Goodman Joanne, Hagger Graham N. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7604–7609. doi: 10.1073/pnas.112059299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lahoua Z., Astruc M. E., Barjon J. N., Michel F., Crastes de Paulet A. Mechanism of the activation of arachidonic acid release by oxysterols in NRK 49F cells: role of calcium. Cell Signal. 1989;1(6):569–576. doi: 10.1016/0898-6568(89)90065-x. [DOI] [PubMed] [Google Scholar]
  18. Landis Mark S., Patel Hansa V., Capone John P. Oxysterol activators of liver X receptor and 9-cis-retinoic acid promote sequential steps in the synthesis and secretion of tumor necrosis factor-alpha from human monocytes. J Biol Chem. 2001 Dec 10;277(7):4713–4721. doi: 10.1074/jbc.M108807200. [DOI] [PubMed] [Google Scholar]
  19. Lehmann J. M., Kliewer S. A., Moore L. B., Smith-Oliver T. A., Oliver B. B., Su J. L., Sundseth S. S., Winegar D. A., Blanchard D. E., Spencer T. A. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem. 1997 Feb 7;272(6):3137–3140. doi: 10.1074/jbc.272.6.3137. [DOI] [PubMed] [Google Scholar]
  20. Luo Y., Liang C. P., Tall A. R. The orphan nuclear receptor LRH-1 potentiates the sterol-mediated induction of the human CETP gene by liver X receptor. J Biol Chem. 2001 Apr 30;276(27):24767–24773. doi: 10.1074/jbc.M100912200. [DOI] [PubMed] [Google Scholar]
  21. Luo Y., Tall A. R. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest. 2000 Feb;105(4):513–520. doi: 10.1172/JCI8573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Miano J. M., Topouzis S., Majesky M. W., Olson E. N. Retinoid receptor expression and all-trans retinoic acid-mediated growth inhibition in vascular smooth muscle cells. Circulation. 1996 May 15;93(10):1886–1895. doi: 10.1161/01.cir.93.10.1886. [DOI] [PubMed] [Google Scholar]
  23. Nishio E., Watanabe Y. Oxysterols induced apoptosis in cultured smooth muscle cells through CPP32 protease activation and bcl-2 protein downregulation. Biochem Biophys Res Commun. 1996 Sep 24;226(3):928–934. doi: 10.1006/bbrc.1996.1452. [DOI] [PubMed] [Google Scholar]
  24. Nitta M., Ku S., Brown C., Okamoto A. Y., Shan B. CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7alpha-hydroxylase gene. Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6660–6665. doi: 10.1073/pnas.96.12.6660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Panini S. R., Yang L., Rusinol A. E., Sinensky M. S., Bonventre J. V., Leslie C. C. Arachidonate metabolism and the signaling pathway of induction of apoptosis by oxidized LDL/oxysterol. J Lipid Res. 2001 Oct;42(10):1678–1686. [PubMed] [Google Scholar]
  26. Peet D. J., Janowski B. A., Mangelsdorf D. J. The LXRs: a new class of oxysterol receptors. Curr Opin Genet Dev. 1998 Oct;8(5):571–575. doi: 10.1016/s0959-437x(98)80013-0. [DOI] [PubMed] [Google Scholar]
  27. Pentikäinen Markku O., Oksjoki Riina, Oörni Katariina, Kovanen Petri T. Lipoprotein lipase in the arterial wall: linking LDL to the arterial extracellular matrix and much more. Arterioscler Thromb Vasc Biol. 2002 Feb 1;22(2):211–217. doi: 10.1161/hq0102.101551. [DOI] [PubMed] [Google Scholar]
  28. Pomerantz K. B., Lander H. M., Summers B., Hajjar D. P. G-protein-mediated signaling in cholesterol-enriched arterial smooth muscle cells. 2. Role of protein kinase C-delta in the regulation of eicosanoid production. Biochemistry. 1997 Aug 5;36(31):9532–9539. doi: 10.1021/bi963070k. [DOI] [PubMed] [Google Scholar]
  29. Pruzanski W., Stefanski E., Kopilov J., Kuksis A. Mitogenic effect of lipoproteins on human vascular smooth muscle cells: the impact of hydrolysis by gr II A phospholipase A(2). Lab Invest. 2001 May;81(5):757–765. doi: 10.1038/labinvest.3780284. [DOI] [PubMed] [Google Scholar]
  30. Rastinejad F. Retinoid X receptor and its partners in the nuclear receptor family. Curr Opin Struct Biol. 2001 Feb;11(1):33–38. doi: 10.1016/s0959-440x(00)00165-2. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Schroepfer G. J., Jr Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev. 2000 Jan;80(1):361–554. doi: 10.1152/physrev.2000.80.1.361. [DOI] [PubMed] [Google Scholar]
  33. Seillan C. Oxysterol mediated changes in fatty acid distribution and lipid synthesis in cultured bovine aortic smooth muscle cells. Lipids. 1990 Mar;25(3):172–176. doi: 10.1007/BF02544334. [DOI] [PubMed] [Google Scholar]
  34. Singaraja Roshni R., Fievet Catherine, Castro Graciela, James Erick R., Hennuyer Nathalie, Clee Susanne M., Bissada Nagat, Choy Jonathan C., Fruchart Jean-Charles, McManus Bruce M. Increased ABCA1 activity protects against atherosclerosis. J Clin Invest. 2002 Jul;110(1):35–42. doi: 10.1172/JCI15748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Six D. A., Dennis E. A. The expanding superfamily of phospholipase A(2) enzymes: classification and characterization. Biochim Biophys Acta. 2000 Oct 31;1488(1-2):1–19. doi: 10.1016/s1388-1981(00)00105-0. [DOI] [PubMed] [Google Scholar]
  36. Song C., Liao S. Cholestenoic acid is a naturally occurring ligand for liver X receptor alpha. Endocrinology. 2000 Nov;141(11):4180–4184. doi: 10.1210/endo.141.11.7772. [DOI] [PubMed] [Google Scholar]
  37. Spencer T. A., Li D., Russel J. S., Collins J. L., Bledsoe R. K., Consler T. G., Moore L. B., Galardi C. M., McKee D. D., Moore J. T. Pharmacophore analysis of the nuclear oxysterol receptor LXRalpha. J Med Chem. 2001 Mar 15;44(6):886–897. doi: 10.1021/jm0004749. [DOI] [PubMed] [Google Scholar]
  38. Steinberg D. Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem. 1997 Aug 22;272(34):20963–20966. doi: 10.1074/jbc.272.34.20963. [DOI] [PubMed] [Google Scholar]
  39. Tischfield J. A. A reassessment of the low molecular weight phospholipase A2 gene family in mammals. J Biol Chem. 1997 Jul 11;272(28):17247–17250. doi: 10.1074/jbc.272.28.17247. [DOI] [PubMed] [Google Scholar]
  40. Touqui L., Alaoui-El-Azher M. Mammalian secreted phospholipases A2 and their pathophysiological significance in inflammatory diseases. Curr Mol Med. 2001 Dec;1(6):739–754. doi: 10.2174/1566524013363258. [DOI] [PubMed] [Google Scholar]
  41. Venkateswaran A., Laffitte B. A., Joseph S. B., Mak P. A., Wilpitz D. C., Edwards P. A., Tontonoz P. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12097–12102. doi: 10.1073/pnas.200367697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Vine D. F., Mamo C. L., Beilin L. J., Mori T. A., Croft K. D. Dietary oxysterols are incorporated in plasma triglyceride-rich lipoproteins, increase their susceptibility to oxidation and increase aortic cholesterol concentration of rabbits. J Lipid Res. 1998 Oct;39(10):1995–2004. [PubMed] [Google Scholar]
  43. Willy P. J., Umesono K., Ong E. S., Evans R. M., Heyman R. A., Mangelsdorf D. J. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 1995 May 1;9(9):1033–1045. doi: 10.1101/gad.9.9.1033. [DOI] [PubMed] [Google Scholar]
  44. Witztum J. L., Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991 Dec;88(6):1785–1792. doi: 10.1172/JCI115499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wohlfeil E. R., Campbell W. B. 25-hydroxycholesterol increases eicosanoids and alters morphology in cultured pulmonary artery smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol. 1999 Dec;19(12):2901–2908. doi: 10.1161/01.atv.19.12.2901. [DOI] [PubMed] [Google Scholar]
  46. Yamamoto M., Aoyagi M., Fukai N., Matsushima Y., Yamamoto K. Increase in prostaglandin E(2) production by interleukin-1beta in arterial smooth muscle cells derived from patients with moyamoya disease. Circ Res. 1999 Nov 12;85(10):912–918. doi: 10.1161/01.res.85.10.912. [DOI] [PubMed] [Google Scholar]
  47. Yin J., Chaufour X., McLachlan C., McGuire M., White G., King N., Hambly B. Apoptosis of vascular smooth muscle cells induced by cholesterol and its oxides in vitro and in vivo. Atherosclerosis. 2000 Feb;148(2):365–374. doi: 10.1016/s0021-9150(99)00286-5. [DOI] [PubMed] [Google Scholar]
  48. Zhang Y., Repa J. J., Gauthier K., Mangelsdorf D. J. Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta. J Biol Chem. 2001 Sep 18;276(46):43018–43024. doi: 10.1074/jbc.M107823200. [DOI] [PubMed] [Google Scholar]

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

RESOURCES