Abstracts (complete list) - Wissenschaft Online

Otilia Postea, Christian Weber, Andreas Ludwig
Homocysteine-induced adhesive and scavenger activity of
endothelial cells involves upregulation of the transmembrane
chemokine CXCL16 by a PPAR-gamma dependent mechanism
Hyperhomocysteinemia induces endothelial dysfunction and promotes atherosclerotic
vascular disease. Infiltrates of activated macrophages and T cells are observed in
human and experimental atherosclerotic lesions. Enrollment of these cells to lesions is
guided by endothelial-leukocyte adhesion molecules and chemoattractants. The CXCL16
chemokine is playing a double role, acting as adhesion molecule by interacting with its
receptor, CXCR6 and as scavenger for oxidized LDL (oxLDL). As the adhesion of
leukocytes to activated endothelial cells (EC) and uptake of modified lipids are crucial
stages for the development of atherosclerosis, we investigated the effect of
homocysteine (Hcy) on the expression and function of CXCL16 chemokine on cultured
EC (EA.hy 926 cells). Incubation of EC with different pathophysiological relevant
concentrations of L-Hcy (50 to 200•M) dose-dependently increased T cell adhesion to
EC as demonstrated in a static adhesion assay. In contrast, D-Hcy and L-cysteine have
no significant effect. Furthermore, stimulation with L-Hcy increased binding of DiI-oxLDL
to EC as detected by flow cytometry. L-Hcy-stimulated EC also show a significant
increase in CXCL16 mRNA and surface expression. Pretreatment of EC with an anti-
CXCL16 monoclonal antibody reduces T cell adhesion to Hcy-incubated EC and uptake of
DiI-oxLDL, suggesting that Hcy may influence leukocyte-endothelial cell interaction and
lipid uptake via the modulation of CXCL16 expression. Antioxidants (Tiron 2,5mM) and
Pioglitazone (100 •M) significantly reduce Hcy´s stimulatory effect indicating that
induction of CXCL16 by Hcy involves the disruption of the PPAR-gamma defense
mechanism against oxidative stress. These data suggest that upregulation of CXCL16 in
response to homocystemia promotes increased adhesion of CXCR6 expressing
circulating T cells and scavenging of modified lipids, both events critically implicated in
the formation and progression of atherosclerotic lesions.