Epoxyeicosatrienoic acids regulate Trp channel-dependent Ca2+ signaling and hyperpolarization in endothelial cells

Ingrid Fleming, Alexandra Rueben, Rüdiger Popp, Beate Fisslthaler, Susanne Schrodt, Anna Sander, Judith Haendeler, John R. Falck, Christophe Morisseau, Bruce D. Hammock, Rudi Busse

Research output: Contribution to journalArticlepeer-review

149 Scopus citations


OBJECTIVE - An initial step in endothelium-derived hyperpolarizing factor-mediated responses is endothelial cell hyperpolarization. Here we address the mechanisms by which cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) contribute to this effect in native and cultured endothelial cells. METHODS AND RESULTS - In native CYP2C-expressing endothelial cells, bradykinin elicited a Ca influx that was potentiated by the soluble epoxide hydrolase inhibitor, 1-adamantyl-3-cyclohexylurea (ACU), and attenuated by CYP inhibition. Similar effects were observed in cultured endothelial cells overexpressing CYP2C9, but not in CYP2C9-deficient cells, and were prevented by the EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid as well as by the cAMP antagonist, Rp-cAMPS. The effects on Ca were mirrored by prolongation of the bradykinin-induced hyperpolarization. Ruthenium red and the combination of charybdotoxin and apamin prevented the latter effect, suggesting that Trp channel activation increases Ca influx and prolongs the activation of Ca-dependent K (KCa) channels. Indeed, overexpression of CYP2C9 enhanced the agonist-induced translocation of a TrpC6-V5 fusion protein to caveolin-1-rich areas of the endothelial cell membrane, which was prevented by Rp-cAMPS and mimicked by 11,12-EET. CONCLUSIONS - Elevated EET levels regulate Ca influx into endothelial cells and the subsequent activation of KCa channels, via a cAMP/PKA-dependent mechanism that involves the intracellular translocation of Trp channels.

Original languageEnglish (US)
Pages (from-to)2612-2618
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number12
StatePublished - Dec 2007


  • Caveolae
  • Cytochrome P450
  • Endothelium-derived hyperpolarizing factor
  • Protein kinase A

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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