Cited by 440Eicosanoids and Hypertension PharmacologyNitric Oxide and Endothelin EffectsPharmacogenetics and Drug Metabolism

Endothelium-Derived Hyperpolarizing Factor Synthase (Cytochrome P450 2C9) Is a Functionally Significant Source of Reactive Oxygen Species in Coronary Arteries

Fleming, Ingrid, Michaelis, U. Ruth, Bredenkötter, Daniel, Fisslthaler, Beate, Dehghani, Faramarz, Brandes, Ralf P., Busse, Rudi·2001·Circulation Research

Abstract

Abstract—In the porcine coronary artery, a cytochrome P450 (CYP) isozyme homologous to CYP 2C8/9 has been identified as an endothelium-derived hyperpolarizing factor (EDHF) synthase. As some CYP enzymes are reported to generate reactive oxygen species (ROS), we hypothesized that the coronary EDHF synthase may modulate vascular homeostasis by the simultaneous production of ROS and epoxyeicosatrienoic acids. In bradykinin-stimulated coronary arteries, antisense oligonucleotides against CYP 2C almost abolished EDHF-mediated responses but potentiated nitric oxide (NO)-mediated relaxation. The selective CYP 2C9 inhibitor sulfaphenazole and the superoxide anion (O 2−) scavengers Tiron and nordihydroguaretic acid also induced a leftward shift in the NO-mediated concentration-relaxation curve to bradykinin. CYP activity and O 2−production, determined in microsomes prepared from cells overexpressing CYP 2C9, were almost completely inhibited by sulfaphenazole. Sulfaphenazole did not alter the activity of either CYP 2C8, the leukocyte NADPH oxidase, or xanthine oxidase. ROS generation in coronary artery rings, visualized using either ethidium or dichlorofluorescein fluorescence, was detected under basal conditions. The endothelial signal was attenuated by CYP 2C antisense treatment as well as by sulfaphenazole. In isolated coronary endothelial cells, bradykinin elicited a sulfaphenazole-sensitive increase in ROS production. Although 11,12 epoxyeicosatrienoic acid attenuated the activity of nuclear factor-κB in cultured human endothelial cells, nuclear factor-κB activity was enhanced after the induction or overexpression of CYP 2C9, as was the expression of vascular cell adhesion molecule-1. These results suggest that a CYP isozyme homologous to CYP 2C9 is a physiologically relevant generator of ROS in coronary endothelial cells and modulates both vascular tone and homeostasis.

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Crossref · 10.1161/01.res.88.1.44

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Authors
Fleming, I., Michaelis, U. R., Bredenkötter, D., Fisslthaler, B., Dehghani, F., Brandes, R. P., & Busse, R.
Affiliations
  • Goethe University Frankfurt (DE)
  • From the Institut für Kardiovaskuläre Physiologie (I.F., U.R.M., D.B., B.F., R.P.B., R.B.) and Institut für Anatomie II (F.D.), Klinikum der J.W.G.-Universität, Frankfurt, Germany.
Venue
Circulation Research
Published
2001-01-19
Volume
88
Issue
1
Pages
44-51
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
OpenAlex
W2157646577
Cited by
440
References
42
Citations by year
2026: 1 · 2025: 4 · 2024: 10 · 2023: 10 · 2022: 6 · 2021: 10 · 2020: 6 · 2019: 13 · 2018: 15 · 2017: 12 · 2016: 18 · 2015: 15 · 2014: 18 · 2013: 14 · 2012: 23
FWCI
14.93
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
endothelium-derived hyperpolarizing factor, CYP2C9, cytochrome P450, reactive oxygen species, superoxide, coronary arteries, bradykinin, nitric oxide, epoxyeicosatrienoic acids, sulfaphenazole, antisense oligonucleotides, nuclear factor-kappaB, VCAM-1, endothelial cells, vascular tone, vascular homeostasis
MeSH terms
Cytochrome P450 Family 2, Animals, Bradykinin, Cell Line, Cells, Cultured, Coronary Vessels, Cytochrome P-450 Enzyme System, Dose-Response Relationship, Drug, Endothelium, Vascular, Humans, Nitric Oxide, Oxygenases, Potassium Chloride, Recombinant Fusion Proteins, Sulfaphenazole, Swine, Tumor Necrosis Factor-alpha, Vasodilation, Xanthine Oxidase, 8,11,14-Eicosatrienoic Acid, NF-kappa B, DNA, Antisense, Reactive Oxygen Species, Vascular Cell Adhesion Molecule-1, NADPH Oxidases, 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, In Vitro Techniques

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