Title

Protein phosphatase 2A and Ca2+-activated K+ channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation

Document Type

Article

Publication Date

2007

Abstract

Epoxyeicosatrienoic acids (EETs) are considered to be endothelium-derived hyperpolarizing factors, and are potent activators of the large-conductance, Ca2+-activated K+ (BKCa) channel in vascular smooth muscle. Here, we investigate the signal transduction pathway involved in the activation of BKCa channels by 11,12-EET and 11,12-EET stable analogs in rat mesenteric vascular smooth muscle cells. 11,12-EET and the 11,12-EET analogs, 11-nonyloxy-undec-8(Z)-enoic acid (11,12-ether-EET-8-ZE), 11-(9-hydroxy-nonyloxy)-undec-8(Z)-enoic acid (11,12-ether-EET-8-ZE-OH) and 11,12-trans-oxidoeicosa-8(Z)-enoic acid (11,12-tetra-EET-8-ZE), caused vasorelaxation of mesenteric resistance arteries. Mesenteric myocyte whole-cell (perforated-patch) currents were substantially (∼150%) increased by 11,12-EET and 11,12-EET analogs. Single-channel recordings were conducted to identify the target for 11,12-EET. 11,12-EET and 11,12-EET analogs also increased mesenteric myocyte BKCa channel activity in cell-attached patches. Similar results were obtained in cell-free patches. Baseline mesenteric myocyte BKCa channel activity (NPo) in cell-free patches averaged less than 0.001 at +50 mV and 11,12-EET (1 µmol/L) increased NPo to 0.03 ± 0.02 and 11,12-EET analogs (1 µmol/L) increased NPo to 0.09 ± 0.006. Inhibition of protein phosphatase 2A (PP2A) activity with okadaic acid (10 nmol/L) completely reversed 11,12-EET stimulated BKCa channel activity and greatly attenuated 11,12-ether-EET-8-ZE mesenteric resistance artery vasorelaxation. 11,12-EET and 11,12-EET analogs increased mesenteric myocyte PP2A activity by 3.5-fold. Okadaic acid and the EET inhibitor, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) inhibited the 11,12-EET mediated increase in PP2A activity. These findings provide initial evidence that PP2A activity contributes to 11,12-EET and 11,12-EET analog activation of mesenteric resistant artery BKCa channels and vasorelaxation.

Publication Title

Prostaglandins and Other Lipid Mediators

Volume

83

Issue

42006

First Page

50

Last Page

61

Comments

This article was published in Prostaglandins and Other Lipid Mediators, Volume 83, Issue 42006, Pages 50-61.

The published version is available at http://dx.doi.org/10.1016/j.prostaglandins.2006.09.008.

Copyright © 2007 Elsevier.

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