Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Sep;96(3):1688–1692. doi: 10.1172/JCI118211

Induction of cyclooxygenase-2 in human umbilical vein endothelial cells by lysophosphatidylcholine.

A Zembowicz 1, S L Jones 1, K K Wu 1
PMCID: PMC185798  PMID: 7657841

Abstract

Lysophosphatidylcholine (lysoPC), a component of atherogenic lipoproteins and atherosclerotic lesions, has been recently suggested to play a role in atherogenesis. LysoPC is known to induce several endothelial genes involved in leukocyte recruitment, mitogenesis, and inflammation. Cyclooxygenases (prostaglandin H2 synthases) are rate-limiting enzymes involved in the endothelial synthesis of prostacyclin, an antiplatelet, vasorelaxant, and vasoprotective molecule. We investigated the effect of lysoPC on the endothelial expression of cyclooxygenases. Our results demonstrate that, in cultured human umbilical vein endothelial cells, lysoPC induces cyclooxygenase-2 mRNA and protein levels. Increased expression of cyclooxygenase-2 is accompanied by the enhancement of both basal- and calcium ionophore A23187-induced synthesis of prostacyclin. Nuclear runoff experiments demonstrated an increased rate of transcription of the cyclooxygenase-2 gene by lysoPC. In contrast, lysoPC did not affect the expression of constitutive cyclooxygenase-1. Our results suggest that the induction of endothelial cyclooxygenase-2 by lysoPC may be an important vasoprotective mechanism that limits progression of atherosclerotic lesions and promotes their regression.

Full text

PDF
1688

Images in this article

1689Image
on p.1689
1690Image
on p.1690
1690Image
on p.1690
1690Image
on p.1690

Selected References

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

  1. Bazan N. G., Fletcher B. S., Herschman H. R., Mukherjee P. K. Platelet-activating factor and retinoic acid synergistically activate the inducible prostaglandin synthase gene. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5252–5256. doi: 10.1073/pnas.91.12.5252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. DeWitt D. L. Prostaglandin endoperoxide synthase: regulation of enzyme expression. Biochim Biophys Acta. 1991 May 8;1083(2):121–134. doi: 10.1016/0005-2760(91)90032-d. [DOI] [PubMed] [Google Scholar]
  3. DeWitt D. L., Smith W. L. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1412–1416. doi: 10.1073/pnas.85.5.1412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Debons A. F., Fani K., Jimenez F. A. Enhancement of experimental atherosclerosis by aspirin. J Toxicol Environ Health. 1981 Nov-Dec;8(5-6):899–906. doi: 10.1080/15287398109530124. [DOI] [PubMed] [Google Scholar]
  5. Diaz A., Reginato A. M., Jimenez S. A. Alternative splicing of human prostaglandin G/H synthase mRNA and evidence of differential regulation of the resulting transcripts by transforming growth factor beta 1, interleukin 1 beta, and tumor necrosis factor alpha. J Biol Chem. 1992 May 25;267(15):10816–10822. [PubMed] [Google Scholar]
  6. FitzGerald G. A., Smith B., Pedersen A. K., Brash A. R. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med. 1984 Apr 26;310(17):1065–1068. doi: 10.1056/NEJM198404263101701. [DOI] [PubMed] [Google Scholar]
  7. Flavahan N. A. Lysophosphatidylcholine modifies G protein-dependent signaling in porcine endothelial cells. Am J Physiol. 1993 Mar;264(3 Pt 2):H722–H727. doi: 10.1152/ajpheart.1993.264.3.H722. [DOI] [PubMed] [Google Scholar]
  8. Fletcher B. S., Kujubu D. A., Perrin D. M., Herschman H. R. Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase. J Biol Chem. 1992 Mar 5;267(7):4338–4344. [PubMed] [Google Scholar]
  9. Hemler M., Lands W. E. Purification of the cyclooxygenase that forms prostaglandins. Demonstration of two forms of iron in the holoenzyme. J Biol Chem. 1976 Sep 25;251(18):5575–5579. [PubMed] [Google Scholar]
  10. Herschman H. R. Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. Cancer Metastasis Rev. 1994 Dec;13(3-4):241–256. doi: 10.1007/BF00666095. [DOI] [PubMed] [Google Scholar]
  11. Hla T., Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384–7388. doi: 10.1073/pnas.89.16.7384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Holland J. A., Pritchard K. A., Rogers N. J., Stemerman M. B. Perturbation of cultured human endothelial cells by atherogenic levels of low density lipoprotein. Am J Pathol. 1988 Sep;132(3):474–478. [PMC free article] [PubMed] [Google Scholar]
  13. Hulkower K. I., Wertheimer S. J., Levin W., Coffey J. W., Anderson C. M., Chen T., DeWitt D. L., Crowl R. M., Hope W. C., Morgan D. W. Interleukin-1 beta induces cytosolic phospholipase A2 and prostaglandin H synthase in rheumatoid synovial fibroblasts. Evidence for their roles in the production of prostaglandin E2. Arthritis Rheum. 1994 May;37(5):653–661. doi: 10.1002/art.1780370508. [DOI] [PubMed] [Google Scholar]
  14. Inoue N., Hirata K., Yamada M., Hamamori Y., Matsuda Y., Akita H., Yokoyama M. Lysophosphatidylcholine inhibits bradykinin-induced phosphoinositide hydrolysis and calcium transients in cultured bovine aortic endothelial cells. Circ Res. 1992 Dec;71(6):1410–1421. doi: 10.1161/01.res.71.6.1410. [DOI] [PubMed] [Google Scholar]
  15. Jones D. A., Carlton D. P., McIntyre T. M., Zimmerman G. A., Prescott S. M. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem. 1993 Apr 25;268(12):9049–9054. [PubMed] [Google Scholar]
  16. Kester M., Coroneos E., Thomas P. J., Dunn M. J. Endothelin stimulates prostaglandin endoperoxide synthase-2 mRNA expression and protein synthesis through a tyrosine kinase-signaling pathway in rat mesangial cells. J Biol Chem. 1994 Sep 9;269(36):22574–22580. [PubMed] [Google Scholar]
  17. Kugiyama K., Ohgushi M., Sugiyama S., Murohara T., Fukunaga K., Miyamoto E., Yasue H. Lysophosphatidylcholine inhibits surface receptor-mediated intracellular signals in endothelial cells by a pathway involving protein kinase C activation. Circ Res. 1992 Dec;71(6):1422–1428. doi: 10.1161/01.res.71.6.1422. [DOI] [PubMed] [Google Scholar]
  18. Kujubu D. A., Fletcher B. S., Varnum B. C., Lim R. W., Herschman H. R. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991 Jul 15;266(20):12866–12872. [PubMed] [Google Scholar]
  19. Kume N., Cybulsky M. I., Gimbrone M. A., Jr Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest. 1992 Sep;90(3):1138–1144. doi: 10.1172/JCI115932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kume N., Gimbrone M. A., Jr Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells. J Clin Invest. 1994 Feb;93(2):907–911. doi: 10.1172/JCI117047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Maier J. A., Barenghi L., Bradamante S., Pagani F. Modulators of oxidized LDL-induced hyperadhesiveness in human endothelial cells. Biochem Biophys Res Commun. 1994 Oct 28;204(2):673–677. doi: 10.1006/bbrc.1994.2512. [DOI] [PubMed] [Google Scholar]
  22. Mehta J. L., Lawson D., Mehta P., Saldeen T. Increased prostacyclin and thromboxane A2 biosynthesis in atherosclerosis. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4511–4515. doi: 10.1073/pnas.85.12.4511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Merlie J. P., Fagan D., Mudd J., Needleman P. Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase). J Biol Chem. 1988 Mar 15;263(8):3550–3553. [PubMed] [Google Scholar]
  24. Moncada S., Gryglewski R., Bunting S., Vane J. R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976 Oct 21;263(5579):663–665. doi: 10.1038/263663a0. [DOI] [PubMed] [Google Scholar]
  25. Morris J. K., Richards J. S. Hormone induction of luteinization and prostaglandin endoperoxide synthase-2 involves multiple cellular signaling pathways. Endocrinology. 1993 Aug;133(2):770–779. doi: 10.1210/endo.133.2.8393774. [DOI] [PubMed] [Google Scholar]
  26. Nakano T., Raines E. W., Abraham J. A., Klagsbrun M., Ross R. Lysophosphatidylcholine upregulates the level of heparin-binding epidermal growth factor-like growth factor mRNA in human monocytes. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1069–1073. doi: 10.1073/pnas.91.3.1069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. doi: 10.1126/science.1411571. [DOI] [PubMed] [Google Scholar]
  28. Parthasarathy S., Quinn M. T., Schwenke D. C., Carew T. E., Steinberg D. Oxidative modification of beta-very low density lipoprotein. Potential role in monocyte recruitment and foam cell formation. Arteriosclerosis. 1989 May-Jun;9(3):398–404. doi: 10.1161/01.atv.9.3.398. [DOI] [PubMed] [Google Scholar]
  29. Parthasarathy S., Steinbrecher U. P., Barnett J., Witztum J. L., Steinberg D. Essential role of phospholipase A2 activity in endothelial cell-induced modification of low density lipoprotein. Proc Natl Acad Sci U S A. 1985 May;82(9):3000–3004. doi: 10.1073/pnas.82.9.3000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pomerantz K. B., Hajjar D. P. Eicosanoids in regulation of arterial smooth muscle cell phenotype, proliferative capacity, and cholesterol metabolism. Arteriosclerosis. 1989 Jul-Aug;9(4):413–429. doi: 10.1161/01.atv.9.4.413. [DOI] [PubMed] [Google Scholar]
  31. Portman O. W., Alexander M. Lysophosphatidylcholine concentrations and metabolism in aortic intima plus inner media: effect of nutritionally induced atherosclerosis. J Lipid Res. 1969 Mar;10(2):158–165. [PubMed] [Google Scholar]
  32. Quinn M. T., Parthasarathy S., Steinberg D. Lysophosphatidylcholine: a chemotactic factor for human monocytes and its potential role in atherogenesis. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2805–2809. doi: 10.1073/pnas.85.8.2805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Radomski M. W., Palmer R. M., Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol. 1987 Nov;92(3):639–646. doi: 10.1111/j.1476-5381.1987.tb11367.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rolland P. H., Jouve R., Pellegrin E., Mercier C., Serradimigni A. Alteration in prostacyclin and prostaglandin E2 production. Correlation with changes in human aortic atherosclerotic disease. Arteriosclerosis. 1984 Jan-Feb;4(1):70–78. doi: 10.1161/01.atv.4.1.70. [DOI] [PubMed] [Google Scholar]
  35. Roshak A., Sathe G., Marshall L. A. Suppression of monocyte 85-kDa phospholipase A2 by antisense and effects on endotoxin-induced prostaglandin biosynthesis. J Biol Chem. 1994 Oct 21;269(42):25999–26005. [PubMed] [Google Scholar]
  36. Ross R. Rous-Whipple Award Lecture. Atherosclerosis: a defense mechanism gone awry. Am J Pathol. 1993 Oct;143(4):987–1002. [PMC free article] [PubMed] [Google Scholar]
  37. Sakai M., Miyazaki A., Hakamata H., Sasaki T., Yui S., Yamazaki M., Shichiri M., Horiuchi S. Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages. J Biol Chem. 1994 Dec 16;269(50):31430–31435. [PubMed] [Google Scholar]
  38. Salmon J. A. A radioimmunoassay for 6-keto-prostaglandin F1alpha. Prostaglandins. 1978 Mar;15(3):383–397. doi: 10.1016/0090-6980(78)90122-3. [DOI] [PubMed] [Google Scholar]
  39. Sanduja S. K., Tsai A. L., Matijevic-Aleksic N., Wu K. K. Kinetics of prostacyclin synthesis in PGHS-1-overexpressed endothelial cells. Am J Physiol. 1994 Nov;267(5 Pt 1):C1459–C1466. doi: 10.1152/ajpcell.1994.267.5.C1459. [DOI] [PubMed] [Google Scholar]
  40. Smith W. L., Marnett L. J. Prostaglandin endoperoxide synthase: structure and catalysis. Biochim Biophys Acta. 1991 Apr 24;1083(1):1–17. doi: 10.1016/0005-2760(91)90119-3. [DOI] [PubMed] [Google Scholar]
  41. Stoller D. K., Grorud C. B., Michalek V., Buchwald H. Reduction of atherosclerosis with nonsteroidal anti-inflammatory drugs. J Surg Res. 1993 Jan;54(1):7–11. doi: 10.1006/jsre.1993.1002. [DOI] [PubMed] [Google Scholar]
  42. Sun Y. P., Zhu B. Q., Sievers R. E., Isenberg W. M., Parmley W. W. Aspirin inhibits platelet activity but does not attenuate experimental atherosclerosis. Am Heart J. 1993 Jan;125(1):79–86. doi: 10.1016/0002-8703(93)90059-i. [DOI] [PubMed] [Google Scholar]
  43. Szczeklik A., Nizankowski R., Skawinski S., Szczeklik J., Gluszko P., Gryglewski R. J. Successful therapy of advanced arteriosclerosis obliterans with prostacyclin. Lancet. 1979 May 26;1(8126):1111–1114. doi: 10.1016/s0140-6736(79)91792-6. [DOI] [PubMed] [Google Scholar]
  44. Triau J. E., Meydani S. N., Schaefer E. J. Oxidized low density lipoprotein stimulates prostacyclin production by adult human vascular endothelial cells. Arteriosclerosis. 1988 Nov-Dec;8(6):810–818. doi: 10.1161/01.atv.8.6.810. [DOI] [PubMed] [Google Scholar]
  45. Vidaver G. A., Ting A., Lee J. W. Evidence that lysolecithin is an important causal agent of atherosclerosis. J Theor Biol. 1985 Jul 7;115(1):27–41. doi: 10.1016/s0022-5193(85)80005-9. [DOI] [PubMed] [Google Scholar]
  46. Wu K. K., Hatzakis H., Lo S. S., Seong D. C., Sanduja S. K., Tai H. H. Stimulation of de novo synthesis of prostaglandin G/H synthase in human endothelial cells by phorbol ester. J Biol Chem. 1988 Dec 15;263(35):19043–19047. [PubMed] [Google Scholar]
  47. Zembowicz A., Tang J. L., Wu K. K. Transcriptional induction of endothelial nitric oxide synthase type III by lysophosphatidylcholine. J Biol Chem. 1995 Jul 14;270(28):17006–17010. doi: 10.1074/jbc.270.28.17006. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES