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. 1993 Jul;92(1):471–478. doi: 10.1172/JCI116590

Minimally modified low density lipoprotein-induced inflammatory responses in endothelial cells are mediated by cyclic adenosine monophosphate.

F Parhami 1, Z T Fang 1, A M Fogelman 1, A Andalibi 1, M C Territo 1, J A Berliner 1
PMCID: PMC293634  PMID: 8392092

Abstract

We have previously shown that minimally oxidized LDL (MM-LDL) activated endothelial cells to increase their interaction with monocytes but not neutrophils, inducing monocyte but not neutrophil binding and synthesis of monocyte chemotactic protein-1 and monocyte colony-stimulating factor (M-CSF). In the present studies we have examined the signaling pathways by which this monocyte-specific response is induced. Both induction of monocyte binding and mRNA levels for M-CSF by MM-LDL were not inhibited in protein kinase C-depleted endothelial cells. A number of our studies indicate that cAMP is the second messenger for the effects of MM-LDL cited above. Incubation of endothelial cells with MM-LDL caused a 173% increase in intracellular cAMP levels. Agents which increased cAMP levels, including cholera toxin, pertussis toxin, dibutyryl cAMP, and isoproterenol mimicked the actions of MM-LDL. Agents which elevated cAMP were also shown to activate NF kappa B, suggesting a role for this transcription factor in activation of monocyte-endothelial interactions. Although endothelial leukocyte adhesion molecule (ELAM) mRNA synthesis can be regulated by NF kappa B, ELAM was not expressed and ELAM mRNA was only slightly elevated in response to MM-LDL. We present evidence that induction of neutrophil binding by LPS is actually suppressed by agents that elevated cAMP levels.

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Selected References

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

  1. Baeuerle P. A., Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science. 1988 Oct 28;242(4878):540–546. doi: 10.1126/science.3140380. [DOI] [PubMed] [Google Scholar]
  2. Berliner J. A., Territo M. C., Sevanian A., Ramin S., Kim J. A., Bamshad B., Esterson M., Fogelman A. M. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990 Apr;85(4):1260–1266. doi: 10.1172/JCI114562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berliner J. A., Territo M., Almada L., Carter A., Shafonsky E., Fogelman A. M. Monocyte chemotactic factor produced by large vessel endothelial cells in vitro. Arteriosclerosis. 1986 May-Jun;6(3):254–258. doi: 10.1161/01.atv.6.3.254. [DOI] [PubMed] [Google Scholar]
  4. Bevilacqua M. P., Pober J. S., Mendrick D. L., Cotran R. S., Gimbrone M. A., Jr Identification of an inducible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9238–9242. doi: 10.1073/pnas.84.24.9238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bevilacqua M. P., Pober J. S., Wheeler M. E., Cotran R. S., Gimbrone M. A., Jr Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest. 1985 Nov;76(5):2003–2011. doi: 10.1172/JCI112200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bork R. W., Svenson K. L., Mehrabian M., Lusis A. J., Fogelman A. M., Edwards P. A. Mechanisms controlling competence gene expression in murine fibroblasts stimulated with minimally modified LDL. Arterioscler Thromb. 1992 Jul;12(7):800–806. doi: 10.1161/01.atv.12.7.800. [DOI] [PubMed] [Google Scholar]
  7. Carlos T. M., Schwartz B. R., Kovach N. L., Yee E., Rosa M., Osborn L., Chi-Rosso G., Newman B., Lobb R., Rosso M. Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood. 1990 Sep 1;76(5):965–970. [PubMed] [Google Scholar]
  8. Carveth H. J., Shaddy R. E., Whatley R. E., McIntyre T. M., Prescott S. M., Zimmerman G. A. Regulation of platelet-activating factor (PAF) synthesis and PAF-mediated neutrophil adhesion to endothelial cells activated by thrombin. Semin Thromb Hemost. 1992 Jan;18(1):126–134. doi: 10.1055/s-2007-1002417. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Clinton S. K., Underwood R., Hayes L., Sherman M. L., Kufe D. W., Libby P. Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. Am J Pathol. 1992 Feb;140(2):301–316. [PMC free article] [PubMed] [Google Scholar]
  11. Collins S., Caron M. G., Lefkowitz R. J. From ligand binding to gene expression: new insights into the regulation of G-protein-coupled receptors. Trends Biochem Sci. 1992 Jan;17(1):37–39. doi: 10.1016/0968-0004(92)90425-9. [DOI] [PubMed] [Google Scholar]
  12. Collins T., Williams A., Johnston G. I., Kim J., Eddy R., Shows T., Gimbrone M. A., Jr, Bevilacqua M. P. Structure and chromosomal location of the gene for endothelial-leukocyte adhesion molecule 1. J Biol Chem. 1991 Feb 5;266(4):2466–2473. [PubMed] [Google Scholar]
  13. Cushing S. D., Berliner J. A., Valente A. J., Territo M. C., Navab M., Parhami F., Gerrity R., Schwartz C. J., Fogelman A. M. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5134–5138. doi: 10.1073/pnas.87.13.5134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. DiCorleto P. E., de la Motte C. A. Thrombin causes increased monocytic-cell adhesion to endothelial cells through a protein kinase C-dependent pathway. Biochem J. 1989 Nov 15;264(1):71–77. doi: 10.1042/bj2640071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Engelhard V. H., Esko J. D., Storm D. R., Glaser M. Modification of adenylate cyclase activity in LM cells by manipulation of the membrane phospholipid composition in vivo. Proc Natl Acad Sci U S A. 1976 Dec;73(12):4482–4486. doi: 10.1073/pnas.73.12.4482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Flavahan N. A., Vanhoutte P. M. G-proteins and endothelial responses. Blood Vessels. 1990;27(2-5):218–229. doi: 10.1159/000158813. [DOI] [PubMed] [Google Scholar]
  17. Fogelman A. M., Shechter I., Seager J., Hokom M., Child J. S., Edwards P. A. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2214–2218. doi: 10.1073/pnas.77.4.2214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gerrity R. G., Naito H. K., Richardson M., Schwartz C. J. Dietary induced atherogenesis in swine. Morphology of the intima in prelesion stages. Am J Pathol. 1979 Jun;95(3):775–792. [PMC free article] [PubMed] [Google Scholar]
  19. Ghosh S., Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature. 1990 Apr 12;344(6267):678–682. doi: 10.1038/344678a0. [DOI] [PubMed] [Google Scholar]
  20. Hoff H. F., Whitaker T. E., O'Neil J. Oxidation of low density lipoprotein leads to particle aggregation and altered macrophage recognition. J Biol Chem. 1992 Jan 5;267(1):602–609. [PubMed] [Google Scholar]
  21. Kita T., Nagano Y., Yokode M., Ishii K., Kume N., Ooshima A., Yoshida H., Kawai C. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5928–5931. doi: 10.1073/pnas.84.16.5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kosugi K., Morel D. W., DiCorleto P. E., Chisolm G. M. Toxicity of oxidized low-density lipoprotein to cultured fibroblasts is selective for S phase of the cell cycle. J Cell Physiol. 1987 Mar;130(3):311–320. doi: 10.1002/jcp.1041300302. [DOI] [PubMed] [Google Scholar]
  23. Krebs E. G. The Albert Lasker Medical Awards. Role of the cyclic AMP-dependent protein kinase in signal transduction. JAMA. 1989 Oct 6;262(13):1815–1818. doi: 10.1001/jama.262.13.1815. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Lane T. A., Lamkin G. E., Wancewicz E. V. Protein kinase C inhibitors block the enhanced expression of intercellular adhesion molecule-1 on endothelial cells activated by interleukin-1, lipopolysaccharide and tumor necrosis factor. Biochem Biophys Res Commun. 1990 Nov 15;172(3):1273–1281. doi: 10.1016/0006-291x(90)91587-i. [DOI] [PubMed] [Google Scholar]
  26. Laychock S. G. Coordinate interactions of cyclic nucleotide and phospholipid metabolizing pathways in calcium-dependent cellular processes. Curr Top Cell Regul. 1989;30:203–242. doi: 10.1016/b978-0-12-152830-0.50009-8. [DOI] [PubMed] [Google Scholar]
  27. Liao F., Berliner J. A., Mehrabian M., Navab M., Demer L. L., Lusis A. J., Fogelman A. M. Minimally modified low density lipoprotein is biologically active in vivo in mice. J Clin Invest. 1991 Jun;87(6):2253–2257. doi: 10.1172/JCI115261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Luscinskas F. W., Brock A. F., Arnaout M. A., Gimbrone M. A., Jr Endothelial-leukocyte adhesion molecule-1-dependent and leukocyte (CD11/CD18)-dependent mechanisms contribute to polymorphonuclear leukocyte adhesion to cytokine-activated human vascular endothelium. J Immunol. 1989 Apr 1;142(7):2257–2263. [PubMed] [Google Scholar]
  29. Mattila P. Protein kinase C subtypes in endothelial cells. FEBS Lett. 1991 Sep 2;289(1):86–90. doi: 10.1016/0014-5793(91)80914-o. [DOI] [PubMed] [Google Scholar]
  30. Montgomery K. F., Osborn L., Hession C., Tizard R., Goff D., Vassallo C., Tarr P. I., Bomsztyk K., Lobb R., Harlan J. M. Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6523–6527. doi: 10.1073/pnas.88.15.6523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Moss J., Vaughan M. ADP-ribosylation of guanyl nucleotide-binding regulatory proteins by bacterial toxins. Adv Enzymol Relat Areas Mol Biol. 1988;61:303–379. doi: 10.1002/9780470123072.ch6. [DOI] [PubMed] [Google Scholar]
  32. Nelken N. A., Coughlin S. R., Gordon D., Wilcox J. N. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991 Oct;88(4):1121–1127. doi: 10.1172/JCI115411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  34. O'Brian C. A., Ward N. E., Weinstein I. B., Bull A. W., Marnett L. J. Activation of rat brain protein kinase C by lipid oxidation products. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1374–1380. doi: 10.1016/s0006-291x(88)81293-2. [DOI] [PubMed] [Google Scholar]
  35. Oishi K., Raynor R. L., Charp P. A., Kuo J. F. Regulation of protein kinase C by lysophospholipids. Potential role in signal transduction. J Biol Chem. 1988 May 15;263(14):6865–6871. [PubMed] [Google Scholar]
  36. Osborn L., Kunkel S., Nabel G. J. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. doi: 10.1073/pnas.86.7.2336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pohlman T. H., Stanness K. A., Beatty P. G., Ochs H. D., Harlan J. M. An endothelial cell surface factor(s) induced in vitro by lipopolysaccharide, interleukin 1, and tumor necrosis factor-alpha increases neutrophil adherence by a CDw18-dependent mechanism. J Immunol. 1986 Jun 15;136(12):4548–4553. [PubMed] [Google Scholar]
  38. Rajavashisth T. B., Andalibi A., Territo M. C., Berliner J. A., Navab M., Fogelman A. M., Lusis A. J. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature. 1990 Mar 15;344(6263):254–257. doi: 10.1038/344254a0. [DOI] [PubMed] [Google Scholar]
  39. Reithmann C., Gierschik P., Jakobs K. H. Stimulation and inhibition of adenylyl cyclase. Symp Soc Exp Biol. 1990;44:207–224. [PubMed] [Google Scholar]
  40. Rollins B. J., Yoshimura T., Leonard E. J., Pober J. S. Cytokine-activated human endothelial cells synthesize and secrete a monocyte chemoattractant, MCP-1/JE. Am J Pathol. 1990 Jun;136(6):1229–1233. [PMC free article] [PubMed] [Google Scholar]
  41. Ross R. The pathogenesis of atherosclerosis--an update. N Engl J Med. 1986 Feb 20;314(8):488–500. doi: 10.1056/NEJM198602203140806. [DOI] [PubMed] [Google Scholar]
  42. Shimokawa H., Flavahan N. A., Vanhoutte P. M. Loss of endothelial pertussis toxin-sensitive G protein function in atherosclerotic porcine coronary arteries. Circulation. 1991 Feb;83(2):652–660. doi: 10.1161/01.cir.83.2.652. [DOI] [PubMed] [Google Scholar]
  43. Shirakawa F., Chedid M., Suttles J., Pollok B. A., Mizel S. B. Interleukin 1 and cyclic AMP induce kappa immunoglobulin light-chain expression via activation of an NF-kappa B-like DNA-binding protein. Mol Cell Biol. 1989 Mar;9(3):959–964. doi: 10.1128/mcb.9.3.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Shirakawa F., Mizel S. B. In vitro activation and nuclear translocation of NF-kappa B catalyzed by cyclic AMP-dependent protein kinase and protein kinase C. Mol Cell Biol. 1989 Jun;9(6):2424–2430. doi: 10.1128/mcb.9.6.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sparrow C. P., Parthasarathy S., Steinberg D. Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell-mediated oxidative modification. J Lipid Res. 1988 Jun;29(6):745–753. [PubMed] [Google Scholar]
  46. Spengler R. N., Spengler M. L., Lincoln P., Remick D. G., Strieter R. M., Kunkel S. L. Dynamics of dibutyryl cyclic AMP- and prostaglandin E2-mediated suppression of lipopolysaccharide-induced tumor necrosis factor alpha gene expression. Infect Immun. 1989 Sep;57(9):2837–2841. doi: 10.1128/iai.57.9.2837-2841.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Steinbrecher U. P. Oxidation of human low density lipoprotein results in derivatization of lysine residues of apolipoprotein B by lipid peroxide decomposition products. J Biol Chem. 1987 Mar 15;262(8):3603–3608. [PubMed] [Google Scholar]
  48. Stelzner T. J., Weil J. V., O'Brien R. F. Role of cyclic adenosine monophosphate in the induction of endothelial barrier properties. J Cell Physiol. 1989 Apr;139(1):157–166. doi: 10.1002/jcp.1041390122. [DOI] [PubMed] [Google Scholar]
  49. Sung C. P., Arleth A. J., Storer B., Feuerstein G. Z. Modulation of U937 cell adhesion to vascular endothelial cells by cyclic AMP. Life Sci. 1991;49(5):375–382. doi: 10.1016/0024-3205(91)90445-h. [DOI] [PubMed] [Google Scholar]
  50. Taylor C. W. The role of G proteins in transmembrane signalling. Biochem J. 1990 Nov 15;272(1):1–13. doi: 10.1042/bj2720001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Visvanathan K. V., Goodbourn S. Double-stranded RNA activates binding of NF-kappa B to an inducible element in the human beta-interferon promoter. EMBO J. 1989 Apr;8(4):1129–1138. doi: 10.1002/j.1460-2075.1989.tb03483.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Ylä-Herttuala S., Lipton B. A., Rosenfeld M. E., Särkioja T., Yoshimura T., Leonard E. J., Witztum J. L., Steinberg D. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5252–5256. doi: 10.1073/pnas.88.12.5252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Ylä-Herttuala S., Palinski W., Rosenfeld M. E., Parthasarathy S., Carew T. E., Butler S., Witztum J. L., Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989 Oct;84(4):1086–1095. doi: 10.1172/JCI114271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Young S., Parker P. J., Ullrich A., Stabel S. Down-regulation of protein kinase C is due to an increased rate of degradation. Biochem J. 1987 Jun 15;244(3):775–779. doi: 10.1042/bj2440775. [DOI] [PMC free article] [PubMed] [Google Scholar]

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