Published online before print February 28, 2002, doi: 10.1161/01.ATV.0000014221.30108.08
© 2002 American Heart Association, Inc.
Vascular Biology |
Homocysteine Upregulates Vascular Cell Adhesion Molecule-1 Expression in Cultured Human Aortic Endothelial Cells and Enhances Monocyte Adhesion
From the Laboratory of Cell Biology (M.D.S., R.J.T., M.D., P.I.L.), Department of Medicine, University of Wisconsin Medical School, Milwaukee; the Department of Cell and Developmental Biology and the Department of Ophthalmology (M.D.S., J.T.R.), Oregon Health Sciences University, Portland; the Laboratory of Cell Biology (G.L., P.I.L.), Department of Medicine, University of Wisconsin Medical School, Madison; and the School of Biomedical Engineering, Science, and Health Systems (P.I.L.), Drexel University, Philadelphia, Pa.
Correspondence to Peter I. Lelkes, PhD, School of Biomedical Engineering, Science and Health Systems, Drexel University, Commonwealth Hall 7-721, 3141 Chestnut St, Philadelphia, PA 19104. E-mail pilelkes@ drexel.edu
Elevated plasma homocysteine is an independent risk factor for atherosclerosis. We hypothesized that homocysteine enhances monocyte/human aortic endothelial cell (HAEC) interactions, a pivotal early event in atherogenesis, by upregulating endothelial adhesion molecules. After incubation of cultured HAECs with reduced DL-homocysteine for up to 24 hours, adhesion of human monocytes to homocysteine-stimulated HAECs was significantly upregulated in a time- and dose-dependent fashion. Pretreatment of HAECs with 100 µmol/L homocysteine caused a 4.5-fold increase in the adhesion of normal human monocytes (P<0.001). Similarly, adhesion of monocytic U937 cells was maximally elevated by 3.5-fold at 100 µmol/L homocysteine (P<0.001). In support of our hypothesis, vascular cell adhesion molecule (VCAM)-1 mRNA expression increased 5-fold in HAECs after 3 hours of treatment with 100 µ mol/L homocysteine, as assessed by quantitative reverse transcription– polymerase chain reaction. Neutralizing antibody studies confirmed the involvement of VCAM-1 in mediating monocyte adhesion to homocysteine-stimulated HAECs. Coincubation of HAECs with homocysteine and tumor necrosis factor-
synergistically elevated monocyte adhesion as well as VCAM-1 protein expression, with the latter evaluated by flow cytometry. Preincubation of HAECs with cyclooxygenase inhibitors completely abrogated homocysteine-induced monocyte adhesion, whereas scavenging reactive oxygen species and the elevation of NO caused partial inhibition only. These data support the notion that the proinflammatory effects of homocysteine may have important implications in atherogenesis.
Key Words: human aortic endothelial cells • homocysteine • monocyte adhesion • vascular cell adhesion molecule-1 • cyclooxygenase
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