Endothelin-1 induces cyclooxygenase-2 expression and generation of reactive oxygen species in endothelial cells

J Cardiovasc Pharmacol. 2004 Nov:44 Suppl 1:S332-5. doi: 10.1097/01.fjc.0000166267.17174.0e.

Abstract

Since both endothelin-1 (ET-1) and aldosterone have been shown to induce expression of several pro-inflammatory genes, including cyclooxygenase-2 (COX-2), in the vasculature as a cardiovascular risk hormone, the present study was undertaken to examine the effects of ET-1 and aldosterone on COX-2 gene expression as measured by a real-time reverse transcriptase-polymerase chain reaction in aortic endothelial cells. Treatment with ET-1(10 M) markedly upregulated COX-2 mRNA levels in rat endothelial cells, whereas aldosterone (10 M) did not show any effect. The ET-1-induced COX-2 upregulation was inhibited by pretreatment with a non-selective endothelin receptor antagonist (TAK044), a protein kinase C inhibitor (GF109203X), and a MEK inhibitor (PD98059). Furthermore, ET-1 increased intracellular reactive oxygen species generation as estimated by the measurement of dichlorofluorescein fluorescence, whose effect was blocked by a COX-2 inhibitor (NS398). Our data show that ET-1 induces COX-2 upregulation in rat endothelial cells via a protein kinase C-dependent and extracellular signal-regulated kinase-dependent pathway, which may largely contribute to the generation of intracellular reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / metabolism
  • Animals
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology*
  • Endothelin Receptor Antagonists
  • Endothelin-1 / metabolism*
  • Enzyme Induction
  • Flavonoids / pharmacology
  • Indoles / pharmacology
  • Male
  • Maleimides / pharmacology
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Nitrobenzenes / pharmacology
  • Peptides, Cyclic / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism*
  • Receptors, Endothelin / metabolism
  • Sulfonamides / pharmacology

Substances

  • Cyclooxygenase 2 Inhibitors
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Flavonoids
  • Indoles
  • Maleimides
  • Nitrobenzenes
  • Peptides, Cyclic
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Reactive Oxygen Species
  • Receptors, Endothelin
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • TAK 044
  • Aldosterone
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase Kinases
  • bisindolylmaleimide I
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one