on September 13, 2007
Published online before print September 13, 2007, doi: 10.1161/ATVBAHA.107.152074
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Submitted on October 13, 2006
Accepted on September 2, 2007
Epoxyeicosatrienoic Acids Regulate Trp Channel–Dependent Ca2+ Signaling and Hyperpolarization in Endothelial Cells
Ingrid Fleming *;
From the Vascular Signaling Group, Institut für Kardiovaskuläre Physiologie (I.F., A.R., R.P., B.F., S.S., A.S., R.B.), and Molecular Cardiology (J.H.), Department of Internal Medicine III, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; the Department of Biochemistry (J.R.F.), University of Texas Southwestern Medical Center, Dallas; and the Department of Entomology (C.M., B.D.H.), University of California, Davis.
* To whom correspondence should be addressed. E-mail: fleming{at}em.uni-frankfurt.de.
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 Ca2+ 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 Ca2+ 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 Ca2+ influx and prolongs the activation of Ca2+-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 Ca2+ 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.
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Arterioscler Thromb Vasc Biol 2007 27: 2496-2498.[Extract] [Full Text] [PDF]
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