Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI2 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 PG12 synthesis, vWF secretion and E-selectin expression using the specific MEK inhibitor PD98059. PD98059 dose-dependently attenuated the tyrosine phosphorylation and activation of p42 mapk in response to thrombin or inflammatory cytokines. Inhibition of thrombin-induced p42 mapk activation was paralleled by an inhibitory effect of PD98059 on thrombin-driven PG12 generation but not on vWF secretion or IL-1 alpha/TNF alpha-induced E-selectin expression. These results provide evidence for a key role for p42 mapk in the acute regulation of PG12 synthesis in human endothelial cells and suggest that activation of the MAP kinase cascade is not obligatory for cytokine-stimulated E-selectin expression.
Wheeler-Jones
C P
CP
Vascular Biology Research Centre, King's College London, UK.
May
M J
MJ
Houliston
R A
RA
Pearson
J D
JD
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis* / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014471:Umbilical Veins; D014841:von Willebrand Factor / Q000187:drug effects / Q000378:metabolism*
D019040:E-Selectin; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D011464:Epoprostenol; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D013917:Thrombin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one