Comparative study of vanadate- and phorbol ester-induced cyclo-oxygenase-2 expression in human endothelial cells

Thromb Haemost. 1999 Nov;82(5):1545-52.

Abstract

Our previous study showed that vanadate, an inhibitor of protein tyrosine phosphatases, induced the expression of cyclo-oxygenase (COX)-2 in a protein-tyrosine-kinase (PTK)-dependent manner in human umbilical vein endothelial cells (HUVEC). Here, we further compared the actions of vanadate and phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), on induction of COX-2 with special reference to mitogen-activated protein kinases (MAPKs) in HUVEC. Vanadate induced activation of three families of MAPKs, extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun amino-terminal kinase (JNK) 1, while activation of ERK 1/2 alone was induced by PMA. The former activation by vanadate and the latter one by PMA were inhibited by tyrphostin-47, an inhibitor of PTKs, and by Ro31-8220, a PKC inhibitor, respectively. Either tyrphostin-47, PD98059, a specific inhibitor of the upstream kinase toward ERK1/2, or SB203580, a specific inhibitor of p38, completely suppressed vanadate-induction of COX-2 mRNA and protein. On the other hand, PMA-induction of COX-2 mRNA and protein was abolished by Ro31-8220 or PD98059 but not by SB203580. These data indicate that PMA-induced and PKC-dependent expression of COX-2 requires mainly activation of ERK 1/2 among MAPKs, while activation of both ERK1/2 and p38 or possibly of all three families of MAPKs is necessary for vanadate-induced and PTK-dependent expression of COX-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclooxygenase 2
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / enzymology
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Isoenzymes / biosynthesis*
  • Isoenzymes / genetics
  • MAP Kinase Signaling System / drug effects*
  • Membrane Proteins
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Protein Kinase C / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyridines / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Tyrphostins / pharmacology
  • Vanadates / pharmacology*

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Indoles
  • Isoenzymes
  • Membrane Proteins
  • Pyridines
  • Tyrphostins
  • tyrphostin 47
  • Vanadates
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Protein-Tyrosine Kinases
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Ro 31-8220