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PMID: 11216856 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Homocysteine stimulates the expression of monocyte chemoattractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis.

Molecular and cellular biochemistry ·Vol. 216 ·No. 1-2 ·2001-01-00 ·Pages 121-8

Sung FL, Slow YL, Wang G, Lynn EG, O K

Abstract

Hyperhomocysteinemia has been identified as an independent risk factor for atherosclerosis. The infiltration of monocytes into the arterial wall is one of the key events during atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall. The mechanism by which increased monocyte infiltration occurs in atherosclerotic lesions in patients with hyperhomocysteinemia has not been delineated. The objective of the present study was to investigate the effect of homocysteine on MCP-1 production in endothelial cells. Cells were incubated with homocysteine. The secretion of MCP-1 protein was significantly increased (195% as compared to the control) in cells treated with pathological concentrations of homocysteine. Such effect was accompanied by an increased expression of MCP-1 mRNA (176% as compared to the control) in endothelial cells which resulted in enhanced monocyte chemotaxis. The p38 MAP kinase as well as other members of the p38 MAP kinase pathway, including MKK3, MKK6, ATF-2 and Elk-1, were activated in homocysteine-treated cells. Homocysteine-induced MCP-1 expression and subsequent monocyte chemotaxis were blocked by a p38 MAP kinase inhibitor (SB203580) suggesting that the p38 MAP kinase pathway might be involved in homocysteine-induced MCP-1 expression in endothelial cells. In contrast, staurosporine, a protein kinase C inhibitor, had no effect on homocysteine-induced MCP-1 expression. In conclusion, our results indicate that homocysteine stimulates MCP-1 expression in endothelial cells leading to enhanced monocyte chemotaxis.

MeSH Terms
Activating Transcription Factor 2 Blotting, Western Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cells, Cultured Chemokine CCL2/biosynthesis Chemotaxis Cyclic AMP Response Element-Binding Protein/metabolism DNA-Binding Proteins Dose-Response Relationship, Drug Endothelium, Vascular/metabolism Enzyme Activation Enzyme Inhibitors/pharmacology Homocysteine/metabolism,physiology Humans Imidazoles/pharmacology MAP Kinase Kinase 3 MAP Kinase Kinase 6 Mitogen-Activated Protein Kinase Kinases/metabolism Mitogen-Activated Protein Kinases/metabolism Monocytes/metabolism Protein Kinase C/antagonists & inhibitors Protein-Tyrosine Kinases/metabolism Proto-Oncogene Proteins/metabolism Pyridines/pharmacology RNA, Messenger/metabolism Staurosporine/pharmacology Time Factors Transcription Factors/metabolism Umbilical Veins/metabolism ets-Domain Protein Elk-1 p38 Mitogen-Activated Protein Kinases
Chemicals
ATF2 protein, human Activating Transcription Factor 2 Chemokine CCL2 Cyclic AMP Response Element-Binding Protein DNA-Binding Proteins ELK1 protein, human Enzyme Inhibitors Imidazoles Proto-Oncogene Proteins Pyridines RNA, Messenger Transcription Factors ets-Domain Protein Elk-1 Homocysteine Protein-Tyrosine Kinases Protein Kinase C Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases MAP Kinase Kinase 3 MAP Kinase Kinase 6 MAP2K3 protein, human MAP2K6 protein, human Mitogen-Activated Protein Kinase Kinases Staurosporine SB 203580
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Sung F L
Department of Pharmacology, Institute of Cardiovascular Science and Medicine, Faculty of Medicine, University of Hong Kong, Hong Kong.
Slow Y L
Wang G
Lynn E G
O K
References (41)
41 references, click to expand
  1. Homocysteine increases nitric oxide synthesis in cytokine-stimulated vascular smooth muscle cells.
    Circulation. 1999 Mar 9;99(9):1230-5 PMID: 10069792
  2. A high glucose concentration stimulates the expression of monocyte chemotactic peptide 1 in human mesangial cells.
    Nephron. 1998;79(1):33-7 PMID: 9609459
  3. Monocyte chemoattractant protein-1 in human atheromatous plaques.
    J Clin Invest. 1991 Oct;88(4):1121-7 PMID: 1843454
  4. Homocysteine stimulates the production and secretion of cholesterol in hepatic cells.
    Biochim Biophys Acta. 1998 Aug 28;1393(2-3):317-24 PMID: 9748642
  5. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes.
    JAMA. 1995 Oct 4;274(13):1049-57 PMID: 7563456
  6. Chemokine gene expression and secretion by cytokine-activated human microvascular endothelial cells. Differential regulation of monocyte chemoattractant protein-1 and interleukin-8 in response to interferon-gamma.
    Am J Pathol. 1994 Oct;145(4):913-21 PMID: 7943180
  7. Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation.
    Arteriosclerosis. 1984 Jul-Aug;4(4):323-40 PMID: 6466191
  8. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. A regulatory role for plasma LDL.
    Arterioscler Thromb Vasc Biol. 1998 Dec;18(12):1983-91 PMID: 9848893
  9. Plasma homocysteine levels and mortality in patients with coronary artery disease.
    N Engl J Med. 1997 Jul 24;337(4):230-6 PMID: 9227928
  10. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation.
    Circulation. 1996 Nov 1;94(9):2154-8 PMID: 8901666
  11. 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):5134-8 PMID: 1695010
  12. Sulfur-containing amino acids in the plasma and urine of homocystinurics.
    Clin Chim Acta. 1967 Mar;15(3):409-20 PMID: 6034417
  13. IL-1beta-induced monocyte chemoattractant protein-1 gene expression in endothelial cells is blocked by proteasome inhibitors.
    Arterioscler Thromb Vasc Biol. 1998 Jun;18(6):934-40 PMID: 9633934
  14. Homocyst(e)ine and arterial occlusive diseases.
    J Intern Med. 1994 Dec;236(6):603-17 PMID: 7989896
  15. The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-alpha-induced expression of monocyte-chemoattractant protein-1 in endothelial cells.
    Blood. 1999 Feb 1;93(3):857-65 PMID: 9920834
  16. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions.
    Am J Pathol. 1981 May;103(2):181-90 PMID: 7234961
  17. Human peritoneal monocytic cells: lipoprotein uptake and foam cell formation.
    Life Sci. 1998;62(6):501-13 PMID: 9464462
  18. Oxidized low density lipoprotein and very low density lipoprotein enhance expression of monocyte chemoattractant protein-1 in rabbit peritoneal exudate macrophages.
    Atherosclerosis. 1997 Aug;133(1):31-6 PMID: 9258404
  19. The expression of monocyte chemotactic protein (MCP-1) in human vascular endothelium in vitro and in vivo.
    Mol Cell Biochem. 1993 Sep 8;126(1):61-8 PMID: 8107690
  20. Rapid quantitation of neutrophil chemotaxis: use of a polyvinylpyrrolidone-free polycarbonate membrane in a multiwell assembly.
    J Immunol Methods. 1980;37(1):39-45 PMID: 7000913
  21. Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease.
    Curr Opin Lipidol. 1997 Feb;8(1):28-34 PMID: 9127708
  22. Lysophosphatidylcholine stimulates the release of arachidonic acid in human endothelial cells.
    J Biol Chem. 1998 Mar 20;273(12 ):6830-6 PMID: 9506985
  23. The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer.
    J Clin Invest. 1995 May;95(5):2391-6 PMID: 7738202
  24. Lysophosphatidylcholine stimulates the expression and production of MCP-1 by human vascular endothelial cells.
    Metabolism. 1996 May;45(5):559-64 PMID: 8622597
  25. Interleukin-1beta regulation of inducible nitric oxide synthase and cyclooxygenase-2 involves the p42/44 and p38 MAPK signaling pathways in cardiac myocytes.
    Hypertension. 1999 Jan;33(1 Pt 2):276-82 PMID: 9931117
  26. Detection of monocyte chemoattractant protein-1 in human atherosclerotic lesions by an anti-monocyte chemoattractant protein-1 monoclonal antibody.
    Hum Pathol. 1993 May;24(5):534-9 PMID: 7684023
  27. Homocysteine and cardiovascular disease.
    Annu Rev Med. 1998;49:31-62 PMID: 9509248
  28. Cytokine-activated human endothelial cells synthesize and secrete a monocyte chemoattractant, MCP-1/JE.
    Am J Pathol. 1990 Jun;136(6):1229-33 PMID: 2113354
  29. Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells.
    FASEB J. 1997 Jul;11(8):703-11 PMID: 9240971
  30. Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures.
    J Neurosci. 1998 Mar 1;18(5):1633-41 PMID: 9464988
  31. Mechanisms in intimal monocyte-macrophage recruitment. A special role for monocyte chemotactic protein-1.
    Circulation. 1992 Dec;86(6 Suppl):III20-5 PMID: 1424047
  32. Elevated levels of homocysteine increase IL-6 production in monocytic Mono Mac 6 cells.
    Blood Coagul Fibrinolysis. 2000 Mar;11(2):159-64 PMID: 10759009
  33. Homocysteine theory of arteriosclerosis.
    Atherosclerosis. 1975 Sep-Oct;22(2):215-27 PMID: 1191372
  34. The pathogenesis of atherosclerosis: a perspective for the 1990s.
    Nature. 1993 Apr 29;362(6423):801-9 PMID: 8479518
  35. Release of chemoattractants for human monocytes from endothelial cells by interaction with neutrophils.
    Cardiovasc Res. 1998 May;38(2):516-21 PMID: 9709414
  36. Homocysteinemia: association of a metabolic disorder with vascular disease and thrombosis.
    Thromb Res. 1993 Sep 1;71(5):337-59 PMID: 8236162
  37. Homocystinemia. Vascular injury and arterial thrombosis.
    N Engl J Med. 1974 Sep 12;291(11):537-43 PMID: 4212055
  38. Hyperhomocysteinemia: an independent risk factor for vascular disease.
    N Engl J Med. 1991 Apr 25;324(17):1149-55 PMID: 2011158
  39. 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):5252-6 PMID: 2052604
  40. Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease.
    Arterioscler Thromb. 1991 Sep-Oct;11(5):1129-36 PMID: 1911700
  41. Homocysteine and vascular disease.
    Nat Med. 1996 Apr;2(4):386-9 PMID: 8597939
Article Info
Journal
Molecular and cellular biochemistry
Abbr.
Mol Cell Biochem
ISSN
0300-8177
DOI
10.1023/a:1017383916068
Published
2001-01-00
Pages
121-8
Language
English
Region
Netherlands
NLM ID
0364456
Subset
IM
External Links
PubMed source DOI: 10.1023/a:1017383916068 View journal details
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