SELECTIVE INHIBITION OF VASCULAR CELL ADHESION MOLECULE-1 EXPRESSION BY VERAPAMIL IN HUMAN VASCULAR ENDOTHELIAL CELLS1

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Abstract
Up-regulated expression of adhesion molecules on vascular endothelial cells (ECs) is an initial event in leukocyte adhesion to ECs, which is a crucial step in the process of inflammatory or immune reaction leading to organ transplant rejection. Verapamil and other calcium channel blockers have been reported to improve transplantation outcome and seem to possess immunosuppressive functions. Therefore, we tested the effect of verapamil on adhesion molecule expression of ECs and adherence of leukocytes to ECs. Verapamil was added to replicate human umbilical vein EC cultures, before adding cytokines. Protein and mRNA expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 were measured by cell-ELISA and by Northern blot analysis after stimulation of ECs. Adherence of leukocytes to ECs was analyzed after stimulation of ECs by tumor necrosis factor-α, with pretreatment of verapamil. Verapamil selectively inhibited cytokine-induced protein and mRNA levels of VCAM-1, and suppressed cell adherence between tumor necrosis factor-α-stimulated ECs and mononuclear leukocytes or Molt-4 cells. These results suggest that verapamil may suppress immune response partly via inhibition of VCAM-1 expression on ECs and a certain subset of lymphocytes adherent to ECs.