INHIBITION OF MAP KINASE KINASE (MEK) BLOCKS ENDOTHELIAL PGI(2) RELEASE BUT HAS NO EFFECT ON VON-WILLEBRAND-FACTOR SECRETION OR E-SELECTIN EXPRESSION

We have examined the potential role of MAP kinase in the regulation of endothelial cell PGI(2) synthesis, VWF secretion and E-selectin expre ssion using the specific MEK inhibitor PD98059. PD98059 dose-dependent ly attenuated the tyrosine phosphorylation and activation of p42(mapk) in response to thrombin or inflammatory cytokines. Inhibition of thro mbin-induced p42(mapk) activation was paralleled by an inhibitory effe ct of PD98059 on thrombin-driven PGI(2) generation but not on vWF secr etion or IL-1 alpha/TNF alpha-induced E-selectin expression. These res ults provide evidence for a key role for p42(mapk) in the acute regula tion of PGI(2) synthesis in human endothelial cells and suggest that a ctivation of the MAP kinase cascade is not obligatory for cytokine-sti mulated E-selectin expression.