Endothelium-derived hyperpolarizing factor in human internal mammary artery is 11,12-epoxyeicosatrienoic acid and causes relaxation by activating smooth muscle BKCa channels

Stephen L. Archer, Ferrante S. Gragasin, Xichen Wu, Shaohua Wang, Sean McMurtry, Daniel H. Kim, Michael Platonov, Arvind Koshal, Kyoko Hashimoto, William B. Campbell, J R Falck, Evangelos D. Michelakis

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

Background - Left internal mammary arteries (LIMAs) synthesize endothelium-derived hyperpolarizing factor (EDHF), a short-lived K+ channel activator that persists after inhibition of nitric oxide (NO) and prostaglandin synthesis. EDHF hyperpolarizes and relaxes smooth muscle cells (SMCs). The identity of EDHF in humans is unknown. We hypothesized that EDHF (1) is 11,12-epoxyeicosatrienoic acid (11,12-EET); (2) is generated by cytochrome P450-2C, CYP450-2C; and (3) causes relaxation by opening SMC large-conductance Ca2+-activated K+ channels (BKCa). Methods and Results - The identity of EDHF and its mechanism of action were assessed in 120 distal human LIMAs and 20 saphenous veins (SVs) obtained during CABG. The predominant EET synthesized by LIMAs is 11,12-EET. Relaxations to exogenous 11,12-EET and endogenous EDHF are of similar magnitudes. Inhibition of EET synthesis by chemically distinct CYP450 inhibitors (17-octadecynoic acid, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide), or a selective EET antagonist (4,15-epoxyeicosa-5(Z)-enoic acid) impairs EDHF relaxation. 11,12-EET activates a BKCa current and hyperpolarizes LIMA SMCs. Inhibitors of BKCa but not inward-rectifier or small-conductance KCa channels abolish relaxation to endogenous EDHF and exogenous 11,12-EET. BKCa and CYP450-2C mRNA and proteins are more abundant in LIMAs than in SVs, perhaps explaining the lack of EDHF activity of the SV. Laser capture microdissection and quantitative RT-PCR demonstrate that BKCa channels are primarily in vascular SMCs, whereas the CYP450-2C enzyme is present in both the endothelium and SMCs. Conclusions - In human LIMAs, EDHF is 11,12-EET produced by an EDHF synthase CYP450-2C and accounting for ≈40% of net endothelial relaxation. 11,12-EET causes relaxation by activating SMC BKCa channels.

Original languageEnglish (US)
Pages (from-to)769-776
Number of pages8
JournalCirculation
Volume107
Issue number5
DOIs
StatePublished - Feb 11 2003

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Mammary Arteries
Endothelium
Smooth Muscle
Smooth Muscle Myocytes
Saphenous Vein
11,12-epoxy-5,8,14-eicosatrienoic acid
Laser Capture Microdissection
Calcium-Activated Potassium Channels
Vascular Smooth Muscle
Cytochrome P-450 Enzyme System
Prostaglandins
Nitric Oxide

Keywords

  • Bypass
  • Cytochromes
  • Ion channels
  • Lasers

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Endothelium-derived hyperpolarizing factor in human internal mammary artery is 11,12-epoxyeicosatrienoic acid and causes relaxation by activating smooth muscle BKCa channels. / Archer, Stephen L.; Gragasin, Ferrante S.; Wu, Xichen; Wang, Shaohua; McMurtry, Sean; Kim, Daniel H.; Platonov, Michael; Koshal, Arvind; Hashimoto, Kyoko; Campbell, William B.; Falck, J R; Michelakis, Evangelos D.

In: Circulation, Vol. 107, No. 5, 11.02.2003, p. 769-776.

Research output: Contribution to journalArticle

Archer, SL, Gragasin, FS, Wu, X, Wang, S, McMurtry, S, Kim, DH, Platonov, M, Koshal, A, Hashimoto, K, Campbell, WB, Falck, JR & Michelakis, ED 2003, 'Endothelium-derived hyperpolarizing factor in human internal mammary artery is 11,12-epoxyeicosatrienoic acid and causes relaxation by activating smooth muscle BKCa channels', Circulation, vol. 107, no. 5, pp. 769-776. https://doi.org/10.1161/01.CIR.0000047278.28407.C2
Archer, Stephen L. ; Gragasin, Ferrante S. ; Wu, Xichen ; Wang, Shaohua ; McMurtry, Sean ; Kim, Daniel H. ; Platonov, Michael ; Koshal, Arvind ; Hashimoto, Kyoko ; Campbell, William B. ; Falck, J R ; Michelakis, Evangelos D. / Endothelium-derived hyperpolarizing factor in human internal mammary artery is 11,12-epoxyeicosatrienoic acid and causes relaxation by activating smooth muscle BKCa channels. In: Circulation. 2003 ; Vol. 107, No. 5. pp. 769-776.
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abstract = "Background - Left internal mammary arteries (LIMAs) synthesize endothelium-derived hyperpolarizing factor (EDHF), a short-lived K+ channel activator that persists after inhibition of nitric oxide (NO) and prostaglandin synthesis. EDHF hyperpolarizes and relaxes smooth muscle cells (SMCs). The identity of EDHF in humans is unknown. We hypothesized that EDHF (1) is 11,12-epoxyeicosatrienoic acid (11,12-EET); (2) is generated by cytochrome P450-2C, CYP450-2C; and (3) causes relaxation by opening SMC large-conductance Ca2+-activated K+ channels (BKCa). Methods and Results - The identity of EDHF and its mechanism of action were assessed in 120 distal human LIMAs and 20 saphenous veins (SVs) obtained during CABG. The predominant EET synthesized by LIMAs is 11,12-EET. Relaxations to exogenous 11,12-EET and endogenous EDHF are of similar magnitudes. Inhibition of EET synthesis by chemically distinct CYP450 inhibitors (17-octadecynoic acid, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide), or a selective EET antagonist (4,15-epoxyeicosa-5(Z)-enoic acid) impairs EDHF relaxation. 11,12-EET activates a BKCa current and hyperpolarizes LIMA SMCs. Inhibitors of BKCa but not inward-rectifier or small-conductance KCa channels abolish relaxation to endogenous EDHF and exogenous 11,12-EET. BKCa and CYP450-2C mRNA and proteins are more abundant in LIMAs than in SVs, perhaps explaining the lack of EDHF activity of the SV. Laser capture microdissection and quantitative RT-PCR demonstrate that BKCa channels are primarily in vascular SMCs, whereas the CYP450-2C enzyme is present in both the endothelium and SMCs. Conclusions - In human LIMAs, EDHF is 11,12-EET produced by an EDHF synthase CYP450-2C and accounting for ≈40{\%} of net endothelial relaxation. 11,12-EET causes relaxation by activating SMC BKCa channels.",
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T1 - Endothelium-derived hyperpolarizing factor in human internal mammary artery is 11,12-epoxyeicosatrienoic acid and causes relaxation by activating smooth muscle BKCa channels

AU - Archer, Stephen L.

AU - Gragasin, Ferrante S.

AU - Wu, Xichen

AU - Wang, Shaohua

AU - McMurtry, Sean

AU - Kim, Daniel H.

AU - Platonov, Michael

AU - Koshal, Arvind

AU - Hashimoto, Kyoko

AU - Campbell, William B.

AU - Falck, J R

AU - Michelakis, Evangelos D.

PY - 2003/2/11

Y1 - 2003/2/11

N2 - Background - Left internal mammary arteries (LIMAs) synthesize endothelium-derived hyperpolarizing factor (EDHF), a short-lived K+ channel activator that persists after inhibition of nitric oxide (NO) and prostaglandin synthesis. EDHF hyperpolarizes and relaxes smooth muscle cells (SMCs). The identity of EDHF in humans is unknown. We hypothesized that EDHF (1) is 11,12-epoxyeicosatrienoic acid (11,12-EET); (2) is generated by cytochrome P450-2C, CYP450-2C; and (3) causes relaxation by opening SMC large-conductance Ca2+-activated K+ channels (BKCa). Methods and Results - The identity of EDHF and its mechanism of action were assessed in 120 distal human LIMAs and 20 saphenous veins (SVs) obtained during CABG. The predominant EET synthesized by LIMAs is 11,12-EET. Relaxations to exogenous 11,12-EET and endogenous EDHF are of similar magnitudes. Inhibition of EET synthesis by chemically distinct CYP450 inhibitors (17-octadecynoic acid, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide), or a selective EET antagonist (4,15-epoxyeicosa-5(Z)-enoic acid) impairs EDHF relaxation. 11,12-EET activates a BKCa current and hyperpolarizes LIMA SMCs. Inhibitors of BKCa but not inward-rectifier or small-conductance KCa channels abolish relaxation to endogenous EDHF and exogenous 11,12-EET. BKCa and CYP450-2C mRNA and proteins are more abundant in LIMAs than in SVs, perhaps explaining the lack of EDHF activity of the SV. Laser capture microdissection and quantitative RT-PCR demonstrate that BKCa channels are primarily in vascular SMCs, whereas the CYP450-2C enzyme is present in both the endothelium and SMCs. Conclusions - In human LIMAs, EDHF is 11,12-EET produced by an EDHF synthase CYP450-2C and accounting for ≈40% of net endothelial relaxation. 11,12-EET causes relaxation by activating SMC BKCa channels.

AB - Background - Left internal mammary arteries (LIMAs) synthesize endothelium-derived hyperpolarizing factor (EDHF), a short-lived K+ channel activator that persists after inhibition of nitric oxide (NO) and prostaglandin synthesis. EDHF hyperpolarizes and relaxes smooth muscle cells (SMCs). The identity of EDHF in humans is unknown. We hypothesized that EDHF (1) is 11,12-epoxyeicosatrienoic acid (11,12-EET); (2) is generated by cytochrome P450-2C, CYP450-2C; and (3) causes relaxation by opening SMC large-conductance Ca2+-activated K+ channels (BKCa). Methods and Results - The identity of EDHF and its mechanism of action were assessed in 120 distal human LIMAs and 20 saphenous veins (SVs) obtained during CABG. The predominant EET synthesized by LIMAs is 11,12-EET. Relaxations to exogenous 11,12-EET and endogenous EDHF are of similar magnitudes. Inhibition of EET synthesis by chemically distinct CYP450 inhibitors (17-octadecynoic acid, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide), or a selective EET antagonist (4,15-epoxyeicosa-5(Z)-enoic acid) impairs EDHF relaxation. 11,12-EET activates a BKCa current and hyperpolarizes LIMA SMCs. Inhibitors of BKCa but not inward-rectifier or small-conductance KCa channels abolish relaxation to endogenous EDHF and exogenous 11,12-EET. BKCa and CYP450-2C mRNA and proteins are more abundant in LIMAs than in SVs, perhaps explaining the lack of EDHF activity of the SV. Laser capture microdissection and quantitative RT-PCR demonstrate that BKCa channels are primarily in vascular SMCs, whereas the CYP450-2C enzyme is present in both the endothelium and SMCs. Conclusions - In human LIMAs, EDHF is 11,12-EET produced by an EDHF synthase CYP450-2C and accounting for ≈40% of net endothelial relaxation. 11,12-EET causes relaxation by activating SMC BKCa channels.

KW - Bypass

KW - Cytochromes

KW - Ion channels

KW - Lasers

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