Increased intracellular calcium transients by calmodulin antagonists differentially modulate tumor necrosis factor-α-induced E-selectin and ICAM-1 expression

We investigated the role of intracellular calcium ([Ca2+]i) in adhesion molecule expression in human umbilical vascular endothelial cells (HUVECs). Calmodulin (CaM) antagonists, W-7, trifluoperazine and chlorpromazine, triggered a rise in [Ca2+]i in HUVECs. In the presence of extracellular Ca2+, thapsigargin pretreatment completely prevented W-7-stimulated increase in [Ca2+]i, indicating that increase is attributable to the release of Ca2+ from internal stores. The increased [Ca2+]i acted as a second messenger to enhance tumor necrosis factor-α (TNF-α)-induced E-selectin and suppress intercellular cell adhesion molecule (ICAM-1) expression. Preincubation of HUVECs with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraaceticacetomethyl ester blocked W-7-mediated effects on E-selectin and ICAM-1. The W-7 effects were paralleled by changes in the respective mRNAs, suggesting regulation at a pretranslational level. These findings indicate that CaM-regulated [Ca2+]i in HUVECs may play an important role in controlling expression of endothelial adhesion molecules involved in atherogenesis.