Document Detail

Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease.
MedLine Citation:
PMID:  11390343     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Proinflammatory cytokines play key roles in atherogenesis and disease progression. Because hyperhomocysteinemia is an independent risk factor for cardiovascular disease, we hypothesized that homocysteine could be atherogenic by altering the expression of specific cytokines in vascular endothelial cells. METHODS AND RESULTS: Northern blot and RNase protection assays showed that DL-homocysteine induced mRNA expression of the proinflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in cultured human aortic endothelial cells (HAECs). Homocysteine had no effect on expression of other cytokines, namely tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, interleukin-1beta, and transforming growth factor-beta. MCP-1 mRNA expression increased 1 hour after homocysteine treatment, reached a maximum within 2 to 4 hours, and declined to basal levels over the next 24 hours. Induction of mRNA expression for both chemokines was observed with as little as 10 micromol/L DL-homocysteine, and maximal expression was achieved with 50 micromol/L DL-homocysteine. Homocysteine also triggered the release of MCP-1 and IL-8 protein from HAECs into the culture medium. The induction was specific for homocysteine, because equimolar concentrations of L-homocystine, L-cysteine, and L-methionine had no effect on mRNA levels and protein release. Furthermore, L-homocysteine induced chemokine expression, but D-homocysteine did not, thus demonstrating enantiomeric specificity. The culture medium from homocysteine-treated HAECs promoted chemotaxis in human peripheral blood monocytes and U937 cells. Anti-human recombinant MCP-1 antibody blocked the migration. CONCLUSIONS: Pathophysiological levels of L-homocysteine alter endothelial cell function by upregulating MCP-1 and IL-8 expression and secretion. This suggests that L-homocysteine may contribute to the initiation and progression of vascular disease by promoting leukocyte recruitment.
R Poddar; N Sivasubramanian; P M DiBello; K Robinson; D W Jacobsen
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  103     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-06-06     Completed Date:  2001-07-12     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2717-23     Citation Subset:  AIM; IM    
Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
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MeSH Terms
Aorta, Thoracic / cytology,  drug effects*,  metabolism
Blotting, Northern
Cells, Cultured
Chemokine CCL2 / genetics,  pharmacology,  secretion*
Chemotaxis / drug effects
Endothelium, Vascular / cytology,  drug effects*,  metabolism
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation / drug effects
Homocysteine / pharmacology*
Interleukin-8 / genetics,  metabolism
RNA, Messenger / drug effects,  genetics,  metabolism
Sulfur Compounds / pharmacology
Time Factors
U937 Cells
Vascular Diseases / genetics,  metabolism,  pathology
Grant Support
Reg. No./Substance:
0/Chemokine CCL2; 0/Interleukin-8; 0/RNA, Messenger; 0/Sulfur Compounds; 454-28-4/Homocysteine

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