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

Christiana Dimitropoulou, Lashondra West, Mary B. Field, Richard E. White, L. Manmohan Reddy, J R Falck, John D. Imig

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)50-61
Number of pages12
JournalProstaglandins and Other Lipid Mediators
Volume83
Issue number1-2
DOIs
StatePublished - Feb 2007

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Calcium-Activated Potassium Channels
Protein Phosphatase 2
Muscle Cells
Mesenteric Arteries
Ether
Okadaic Acid
11,12-epoxy-5,8,14-eicosatrienoic acid
Acids
Vasodilation
Muscle
Vascular Smooth Muscle
Chemical activation
Signal transduction

Keywords

  • Calcium-dependent K channels
  • Eicosanoids
  • Endothelium-derived hyperpolarizing factor
  • Mesenteric
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Protein phosphatase 2A and Ca2+-activated K+ channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation. / Dimitropoulou, Christiana; West, Lashondra; Field, Mary B.; White, Richard E.; Reddy, L. Manmohan; Falck, J R; Imig, John D.

In: Prostaglandins and Other Lipid Mediators, Vol. 83, No. 1-2, 02.2007, p. 50-61.

Research output: Contribution to journalArticle

Dimitropoulou, Christiana ; West, Lashondra ; Field, Mary B. ; White, Richard E. ; Reddy, L. Manmohan ; Falck, J R ; Imig, John D. / Protein phosphatase 2A and Ca2+-activated K+ channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation. In: Prostaglandins and Other Lipid Mediators. 2007 ; Vol. 83, No. 1-2. pp. 50-61.
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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.",
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T1 - Protein phosphatase 2A and Ca2+-activated K+ channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation

AU - Dimitropoulou, Christiana

AU - West, Lashondra

AU - Field, Mary B.

AU - White, Richard E.

AU - Reddy, L. Manmohan

AU - Falck, J R

AU - Imig, John D.

PY - 2007/2

Y1 - 2007/2

N2 - 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.

AB - 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.

KW - Calcium-dependent K channels

KW - Eicosanoids

KW - Endothelium-derived hyperpolarizing factor

KW - Mesenteric

KW - Vascular smooth muscle

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