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. 1988 Mar;81(3):720–729. doi: 10.1172/JCI113377

Stimulated arachidonate metabolism during foam cell transformation of mouse peritoneal macrophages with oxidized low density lipoprotein.

M Yokode 1, T Kita 1, Y Kikawa 1, T Ogorochi 1, S Narumiya 1, C Kawai 1
PMCID: PMC442519  PMID: 3125226

Abstract

Changes in arachidonate metabolism were examined in mouse peritoneal macrophages incubated with various types of lipoproteins. Oxidized low density lipoprotein (LDL) was incorporated by macrophages and stimulated macrophage prostaglandin E2 (PGE2) and leukotriene C4 syntheses, respectively, 10.8- and 10.7-fold higher than by the control. Production of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin, was also stimulated. No stimulation was found with native LDL, which was minimally incorporated by the cells. Acetylated LDL and beta-migrating very low density lipoprotein (beta-VLDL), though incorporated more efficiently than oxidized LDL, also had no stimulatory effect. When oxidized LDL was separated into the lipoprotein-lipid peroxide complex and free lipid peroxides, most of the stimulatory activity was found in the former fraction, indicating that stimulation of arachidonate metabolism in the cell is associated with uptake of the lipoprotein-lipid peroxide complex. These results suggest that peroxidative modification of LDL could contribute to the progression of atheroma by stimulating arachidonate metabolism during incorporation into macrophages.

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Selected References

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

  1. Aehringhaus U., Wölbling R. H., König W., Patrono C., Peskar B. M., Peskar B. A. Release of leukotriene C4 from human polymorphonuclear leucocytes as determined by radioimmunoassay. FEBS Lett. 1982 Sep 6;146(1):111–114. doi: 10.1016/0014-5793(82)80715-1. [DOI] [PubMed] [Google Scholar]
  2. Axline S. G., Reaven E. P. Inhibition of phagocytosis and plasma membrane mobility of the cultivated macrophage by cytochalasin B. Role of subplasmalemmal microfilaments. J Cell Biol. 1974 Sep;62(3):647–659. doi: 10.1083/jcb.62.3.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Basu S. K., Goldstein J. L., Anderson G. W., Brown M. S. Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. Proc Natl Acad Sci U S A. 1976 Sep;73(9):3178–3182. doi: 10.1073/pnas.73.9.3178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bilheimer D. W., Watanabe Y., Kita T. Impaired receptor-mediated catabolism of low density lipoprotein in the WHHL rabbit, an animal model of familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1982 May;79(10):3305–3309. doi: 10.1073/pnas.79.10.3305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bonney R. J., Humes J. L. Physiological and pharmacological regulation of prostaglandin and leukotriene production by macrophages. J Leukoc Biol. 1984 Jan;35(1):1–10. doi: 10.1002/jlb.35.1.1. [DOI] [PubMed] [Google Scholar]
  6. Brown M. S., Goldstein J. L., Krieger M., Ho Y. K., Anderson R. G. Reversible accumulation of cholesteryl esters in macrophages incubated with acetylated lipoproteins. J Cell Biol. 1979 Sep;82(3):597–613. doi: 10.1083/jcb.82.3.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brown M. S., Goldstein J. L. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–261. doi: 10.1146/annurev.bi.52.070183.001255. [DOI] [PubMed] [Google Scholar]
  8. Buja L. M., Kita T., Goldstein J. L., Watanabe Y., Brown M. S. Cellular pathology of progressive atherosclerosis in the WHHL rabbit. An animal model of familial hypercholesterolemia. Arteriosclerosis. 1983 Jan-Feb;3(1):87–101. doi: 10.1161/01.atv.3.1.87. [DOI] [PubMed] [Google Scholar]
  9. Cathcart M. K., Morel D. W., Chisolm G. M., 3rd Monocytes and neutrophils oxidize low density lipoprotein making it cytotoxic. J Leukoc Biol. 1985 Aug;38(2):341–350. doi: 10.1002/jlb.38.2.341. [DOI] [PubMed] [Google Scholar]
  10. Evensen S. A., Galdal K. S., Nilsen E. LDL-induced cytotoxicity and its inhibition by anti-oxidant treatment in cultured human endothelial cells and fibroblasts. Atherosclerosis. 1983 Oct;49(1):23–30. doi: 10.1016/0021-9150(83)90004-7. [DOI] [PubMed] [Google Scholar]
  11. Fainaru M., Mahley R. W., Hamilton R. L., Innerarity T. L. Structural and metabolic heterogeneity of beta-very low density lipoproteins from cholesterol-fed dogs and from humans with type III hyperlipoproteinemia. J Lipid Res. 1982 Jul;23(5):702–714. [PubMed] [Google Scholar]
  12. Feuerstein G. Leukotrienes and the cardiovascular system. Prostaglandins. 1984 May;27(5):781–802. doi: 10.1016/0090-6980(84)90015-7. [DOI] [PubMed] [Google Scholar]
  13. Forte T. M., Nordhausen R. W. Electron microscopy of negatively stained lipoproteins. Methods Enzymol. 1986;128:442–457. doi: 10.1016/0076-6879(86)28086-6. [DOI] [PubMed] [Google Scholar]
  14. GLAVIND J., HARTMANN S., CLEMMESEN J., JESSEN K. E., DAM H. Studies on the role of lipoperoxides in human pathology. II. The presence of peroxidized lipids in the atherosclerotic aorta. Acta Pathol Microbiol Scand. 1952;30(1):1–6. doi: 10.1111/j.1699-0463.1952.tb00157.x. [DOI] [PubMed] [Google Scholar]
  15. Gemsa D., Leser H. G., Seitz M., Deimann W., Bärlin E. Membrane perturbation and stimulation of arachidonic acid metabolism. Mol Immunol. 1982 Oct;19(10):1287–1296. doi: 10.1016/0161-5890(82)90295-4. [DOI] [PubMed] [Google Scholar]
  16. Gerrity R. G. The role of the monocyte in atherogenesis: II. Migration of foam cells from atherosclerotic lesions. Am J Pathol. 1981 May;103(2):191–200. [PMC free article] [PubMed] [Google Scholar]
  17. Goldstein J. L., Ho Y. K., Basu S. K., Brown M. S. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A. 1979 Jan;76(1):333–337. doi: 10.1073/pnas.76.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Goldstein J. L., Ho Y. K., Brown M. S., Innerarity T. L., Mahley R. W. Cholesteryl ester accumulation in macrophages resulting from receptor-mediated uptake and degradation of hypercholesterolemic canine beta-very low density lipoproteins. J Biol Chem. 1980 Mar 10;255(5):1839–1848. [PubMed] [Google Scholar]
  19. Goldstein J. L., Kita T., Brown M. S. Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med. 1983 Aug 4;309(5):288–296. doi: 10.1056/NEJM198308043090507. [DOI] [PubMed] [Google Scholar]
  20. Gryglewski R. J., Dembińska-Kiè A., Zmuda A., Gryglewska T. Prostacyclin and thromboxane A2 biosynthesis capacities of heart, arteries and platelets at various stages of experimental atherosclerosis in rabbits. Atherosclerosis. 1978 Dec;31(4):385–394. doi: 10.1016/0021-9150(78)90133-8. [DOI] [PubMed] [Google Scholar]
  21. HAVEL R. J., EDER H. A., BRAGDON J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. doi: 10.1172/JCI103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hajjar D. P., Weksler B. B., Falcone D. J., Hefton J. M., Tack-Goldman K., Minick C. R. Prostacyclin modulates cholesteryl ester hydrolytic activity by its effect on cyclic adenosine monophosphate in rabbit aortic smooth muscle cells. J Clin Invest. 1982 Sep;70(3):479–488. doi: 10.1172/JCI110639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Heinecke J. W., Baker L., Rosen H., Chait A. Superoxide-mediated modification of low density lipoprotein by arterial smooth muscle cells. J Clin Invest. 1986 Mar;77(3):757–761. doi: 10.1172/JCI112371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Heinecke J. W., Rosen H., Chait A. Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. J Clin Invest. 1984 Nov;74(5):1890–1894. doi: 10.1172/JCI111609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Henriksen T., Mahoney E. M., Steinberg D. Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6499–6503. doi: 10.1073/pnas.78.10.6499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Henriksen T., Mahoney E. M., Steinberg D. Interactions of plasma lipoproteins with endothelial cells. Ann N Y Acad Sci. 1982;401:102–116. doi: 10.1111/j.1749-6632.1982.tb25711.x. [DOI] [PubMed] [Google Scholar]
  27. Hessler J. R., Morel D. W., Lewis L. J., Chisolm G. M. Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis. 1983 May-Jun;3(3):215–222. doi: 10.1161/01.atv.3.3.215. [DOI] [PubMed] [Google Scholar]
  28. Hsueh W., Kuhn C., 3rd, Needleman P. Relationship of prostaglandin secretion by rabbit alveolar macrophages to phagocytosis and lysosomal enzyme release. Biochem J. 1979 Nov 15;184(2):345–354. doi: 10.1042/bj1840345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Humes J. L., Bonney R. J., Pelus L., Dahlgren M. E., Sadowski S. J., Kuehl F. A., Jr, Davies P. Macrophages synthesis and release prostaglandins in response to inflammatory stimuli. Nature. 1977 Sep 8;269(5624):149–151. doi: 10.1038/269149a0. [DOI] [PubMed] [Google Scholar]
  30. Kita T., Brown M. S., Watanabe Y., Goldstein J. L. Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2268–2272. doi: 10.1073/pnas.78.4.2268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kita T., Yokode M., Watanabe Y., Narumiya S., Kawai C. Stimulation of cholesteryl ester synthesis in mouse peritoneal macrophages by cholesterol-rich very low density lipoproteins from the Watanabe heritable hyperlipidemic rabbit, an animal model of familial hypercholesterolemia. J Clin Invest. 1986 May;77(5):1460–1465. doi: 10.1172/JCI112458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  33. Larrue J., Rigaud M., Daret D., Demond J., Durand J., Bricaud H. Prostacyclin production by cultured smooth muscle cells from atherosclerotic rabbit aorta. Nature. 1980 Jun 12;285(5765):480–482. doi: 10.1038/285480a0. [DOI] [PubMed] [Google Scholar]
  34. McIntyre T. M., Zimmerman G. A., Prescott S. M. Leukotrienes C4 and D4 stimulate human endothelial cells to synthesize platelet-activating factor and bind neutrophils. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2204–2208. doi: 10.1073/pnas.83.7.2204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Miller N. E., Yin J. A. Effects of cytochalasin B on low-density lipoproteins metabolism by cultured human fibroblasts. Biochim Biophys Acta. 1978 Jul 25;530(1):145–150. doi: 10.1016/0005-2760(78)90134-0. [DOI] [PubMed] [Google Scholar]
  36. Morel D. W., DiCorleto P. E., Chisolm G. M. Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis. 1984 Jul-Aug;4(4):357–364. doi: 10.1161/01.atv.4.4.357. [DOI] [PubMed] [Google Scholar]
  37. Nathan C. F., Murray H. W., Cohn Z. A. The macrophage as an effector cell. N Engl J Med. 1980 Sep 11;303(11):622–626. doi: 10.1056/NEJM198009113031106. [DOI] [PubMed] [Google Scholar]
  38. Noble R. P. Electrophoretic separation of plasma lipoproteins in agarose gel. J Lipid Res. 1968 Nov;9(6):693–700. [PubMed] [Google Scholar]
  39. Ogorochi T., Narumiya S., Mizuno N., Yamashita K., Miyazaki H., Hayaishi O. Regional distribution of prostaglandins D2, E2, and F2 alpha and related enzymes in postmortem human brain. J Neurochem. 1984 Jul;43(1):71–82. doi: 10.1111/j.1471-4159.1984.tb06680.x. [DOI] [PubMed] [Google Scholar]
  40. Okazaki M., Shiraishi K., Ohno Y., Hara I. High-performance aqueous gel permeation chromatography of serum lipoproteins: selective detection of cholesterol by enzymatic reaction. J Chromatogr. 1981 May 8;223(2):285–293. doi: 10.1016/s0378-4347(00)80100-0. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. Parthasarathy S., Young S. G., Witztum J. L., Pittman R. C., Steinberg D. Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest. 1986 Feb;77(2):641–644. doi: 10.1172/JCI112349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pomerantz K. B., Tall A. R., Feinmark S. J., Cannon P. J. Stimulation of vascular smooth muscle cell prostacyclin and prostaglandin E2 synthesis by plasma high and low density lipoproteins. Circ Res. 1984 May;54(5):554–565. doi: 10.1161/01.res.54.5.554. [DOI] [PubMed] [Google Scholar]
  44. Powell W. S. Rapid extraction of arachidonic acid metabolites from biological samples using octadecylsilyl silica. Methods Enzymol. 1982;86:467–477. doi: 10.1016/0076-6879(82)86218-6. [DOI] [PubMed] [Google Scholar]
  45. Quinn M. T., Parthasarathy S., Steinberg D. Endothelial cell-derived chemotactic activity for mouse peritoneal macrophages and the effects of modified forms of low density lipoprotein. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5949–5953. doi: 10.1073/pnas.82.17.5949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rouzer C. A., Scott W. A., Cohn Z. A., Blackburn P., Manning J. M. Mouse peritoneal macrophages release leukotriene C in response to a phagocytic stimulus. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4928–4932. doi: 10.1073/pnas.77.8.4928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Schuh J., Novogrodsky A., Haschemeyer R. H. Inhibition of lymphocyte mitogenesis by autoxidized low-density lipoprotein. Biochem Biophys Res Commun. 1978 Oct 16;84(3):763–768. doi: 10.1016/0006-291x(78)90770-2. [DOI] [PubMed] [Google Scholar]
  48. Scott W. A., Zrike J. M., Hamill A. L., Kempe J., Cohn Z. A. Regulation of arachidonic acid metabolites in macrophages. J Exp Med. 1980 Aug 1;152(2):324–335. doi: 10.1084/jem.152.2.324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Steinberg D. Lipoproteins and atherosclerosis. A look back and a look ahead. Arteriosclerosis. 1983 Jul-Aug;3(4):283–301. doi: 10.1161/01.atv.3.4.283. [DOI] [PubMed] [Google Scholar]
  50. Steinbrecher U. P., Parthasarathy S., Leake D. S., Witztum J. L., Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3883–3887. doi: 10.1073/pnas.81.12.3883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Stoudemire J. B., Renaud G., Shames D. M., Havel R. J. Impaired receptor-mediated catabolism of low density lipoproteins in fasted rabbits. J Lipid Res. 1984 Jan;25(1):33–39. [PubMed] [Google Scholar]
  52. Vane J. R., Bunting S., Moncada S. Prostacyclin in physiology and pathophysiology. Int Rev Exp Pathol. 1982;23:161–207. [PubMed] [Google Scholar]
  53. Weglicki W. B., Dickens B. F., Mak I. T. Enhanced lysosomal phospholipid degradation and lysophospholipid production due to free radicals. Biochem Biophys Res Commun. 1984 Oct 15;124(1):229–235. doi: 10.1016/0006-291x(84)90941-0. [DOI] [PubMed] [Google Scholar]
  54. Yagi K. A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med. 1976 Apr;15(2):212–216. doi: 10.1016/0006-2944(76)90049-1. [DOI] [PubMed] [Google Scholar]
  55. Yamamoto A., Matsuzawa Y., Kishino B., Hayashi R., Hirobe K., Kikkawa T. Effects of probucol on homozygous cases of familial hypercholesterolemia. Atherosclerosis. 1983 Aug;48(2):157–166. doi: 10.1016/0021-9150(83)90102-8. [DOI] [PubMed] [Google Scholar]
  56. van der Schroeff J. G., Havekes L., Weerheim A. M., Emeis J. J., Vermeer B. J. Suppression of cholesteryl ester accumulation in cultured human monocyte-derived macrophages by lipoxygenase inhibitors. Biochem Biophys Res Commun. 1985 Feb 28;127(1):366–372. doi: 10.1016/s0006-291x(85)80168-6. [DOI] [PubMed] [Google Scholar]

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