PMID- 11390343 OWN - NLM STAT- MEDLINE DCOM- 20010712 LR - 20220311 IS - 1524-4539 (Electronic) IS - 0009-7322 (Linking) VI - 103 IP - 22 DP - 2001 Jun 5 TI - Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease. PG - 2717-23 AB - 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. FAU - Poddar, R AU - Poddar R AD - Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. FAU - Sivasubramanian, N AU - Sivasubramanian N FAU - DiBello, P M AU - DiBello PM FAU - Robinson, K AU - Robinson K FAU - Jacobsen, D W AU - Jacobsen DW LA - eng GR - R01-HL-52334/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Circulation JT - Circulation JID - 0147763 RN - 0 (Chemokine CCL2) RN - 0 (Interleukin-8) RN - 0 (RNA, Messenger) RN - 0 (Sulfur Compounds) RN - 0LVT1QZ0BA (Homocysteine) SB - IM MH - Aorta, Thoracic/cytology/*drug effects/metabolism MH - Blotting, Northern MH - Cells, Cultured MH - Chemokine CCL2/genetics/*metabolism/pharmacology MH - Chemotaxis/drug effects MH - Endothelium, Vascular/cytology/*drug effects/metabolism MH - Enzyme-Linked Immunosorbent Assay MH - Gene Expression Regulation/drug effects MH - Homocysteine/*pharmacology MH - Humans MH - Interleukin-8/genetics/metabolism MH - RNA, Messenger/drug effects/genetics/metabolism MH - Sulfur Compounds/pharmacology MH - Time Factors MH - U937 Cells MH - Vascular Diseases/genetics/metabolism/pathology EDAT- 2001/06/08 10:00 MHDA- 2001/07/13 10:01 CRDT- 2001/06/08 10:00 PHST- 2001/06/08 10:00 [pubmed] PHST- 2001/07/13 10:01 [medline] PHST- 2001/06/08 10:00 [entrez] AID - 10.1161/01.cir.103.22.2717 [doi] PST - ppublish SO - Circulation. 2001 Jun 5;103(22):2717-23. doi: 10.1161/01.cir.103.22.2717.