Lacidipine inhibits the activation of the transcription factor NF-kappa B and the expression of adhesion molecules induced by pro-oxidant signals on endothelial cells

Abstract

The adhesion of monocytes to endothelium, an early event in atherosclerosis is mediated by cell adhesion molecules. Signal-transduction pathways for these binding molecules include the translocation of the transcription factor NF-κB; moreover, intracellularly generated oxygen-derived free radicals play a major role in this process. In this study we evaluated the extent to which lacidipine, a calcium antagonist with antioxidant properties, affects the expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells, induced by different pro-oxidant signals such as oxidized low density lipoprotein (LDL) and tumor necrosis factor-α (TNF-α).

We incubated 5 mmol/l Cu2+-oxidized LDL and TNF-α (2 ng/ml) with human umbilical vein endothelial cells for 48 and 6 h, respectively. ICAM-1, VCAM-1 and E-selectin were measured by flow cytometry. NF-κB was evaluated by electrophoretic mobility shift assay.

The incubation of 5 μmol/l Cu2+-oxidized LDL not only caused a dose-dependent increase in ICAM-1, VCAM-1 and E-selectin (P <0.001), but also synergically increased their TNF-α–induced expression (P <0.001). The addition of lacidipine to human umbilical vein endothelial cells significantly reduced the expression of ICAM-1, VCAM-1 and E-selectin induced by TNF-α alone or with oxidized LDL (P <0.001). The reduction in adhesion molecule expression caused by lacidipine was paralleled by a significant fall in NF-κB translocation.

The results suggest that lacidipine may have prevented NF-κB-mediated adhesion molecule expression by exerting its effects on oxygen-derived free radicals. The results support previous observations that lacidipine may have therapeutic effects in atherosclerosis.