© 2001 American Heart Association, Inc.
Molecular Medicine |
Endothelium-Derived Hyperpolarizing Factor Synthase (Cytochrome P450 2C9) Is a Functionally Significant Source of Reactive Oxygen Species in Coronary Arteries
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.
Correspondence to Ingrid Fleming, PhD, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W.G.-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. E-mail fleming{at}em.uni-frankfurt.de
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
(O2-) scavengers
Tiron and nordihydroguaretic acid also induced a leftward shift in the
NO-mediated concentration-relaxation curve to bradykinin. CYP activity
and O2- 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-
B in cultured human endothelial cells, nuclear
factor-B 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.
Key Words: coronary artery • cytochrome P450 • endothelium-derived hyperpolarizing factor • NADPH oxidase • reactive oxygen species
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S. Shigematsu, S. Ishida, D. C. Gute, and R. J. Korthuis Bradykinin-induced proinflammatory signaling mechanisms Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2676 - H2686. [Abstract] [Full Text] [PDF]
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 D. N. Muller, E. Shagdarsuren, J.-K. Park, R. Dechend, E. Mervaala, F. Hampich, A. Fiebeler, X. Ju, P. Finckenberg, J. Theuer, et al. Immunosuppressive Treatment Protects Against Angiotensin II-Induced Renal Damage Am. J. Pathol., November 1, 2002; 161(5): 1679 - 1693. [Abstract] [Full Text] [PDF]
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Q. Hu, Z.-X. Yu, V. J. Ferrans, K. Takeda, K. Irani, and R. C. Ziegelstein Critical Role of NADPH Oxidase-derived Reactive Oxygen Species in Generating Ca2+ Oscillations in Human Aortic Endothelial Cells Stimulated by Histamine J. Biol. Chem., August 30, 2002; 277(36): 32546 - 32551. [Abstract] [Full Text] [PDF]
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C. Urbich, E. Dernbach, A. Aicher, A. M. Zeiher, and S. Dimmeler CD40 Ligand Inhibits Endothelial Cell Migration by Increasing Production of Endothelial Reactive Oxygen Species Circulation, August 20, 2002; 106(8): 981 - 986. [Abstract] [Full Text] [PDF]
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J. Bauersachs, M. Christ, G. Ertl, U.R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming Cytochrome P450 2C expression and EDHF-mediated relaxation in porcine coronary arteries is increased by cortisol Cardiovasc Res, June 1, 2002; 54(3): 669 - 675. [Abstract] [Full Text] [PDF]
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I. Fleming To Move or Not To Move?: Cytochrome P450 Products and Cell Migration Circ. Res., May 17, 2002; 90(9): 936 - 938. [Full Text] [PDF]
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J. Sun, X. Sui, J. A. Bradbury, D. C. Zeldin, M. S. Conte, and J. K. Liao Inhibition of Vascular Smooth Muscle Cell Migration by Cytochrome P450 Epoxygenase-Derived Eicosanoids Circ. Res., May 17, 2002; 90(9): 1020 - 1027. [Abstract] [Full Text] [PDF]
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M. Potente, U. R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming Cytochrome P450 2C9-induced Endothelial Cell Proliferation Involves Induction of Mitogen-activated Protein (MAP) Kinase Phosphatase-1, Inhibition of the c-Jun N-terminal Kinase, and Up-regulation of Cyclin D1 J. Biol. Chem., May 3, 2002; 277(18): 15671 - 15676. [Abstract] [Full Text] [PDF]
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R. Popp, R. P. Brandes, G. Ott, R. Busse, and I. Fleming Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid Circ. Res., April 19, 2002; 90(7): 800 - 806. [Abstract] [Full Text] [PDF]
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R. Locher, R. P. Brandes, W. Vetter, and M. Barton Native LDL Induces Proliferation of Human Vascular Smooth Muscle Cells via Redox-Mediated Activation of ERK 1/2 Mitogen-Activated Protein Kinases Hypertension, February 1, 2002; 39(2): 645 - 650. [Abstract] [Full Text] [PDF]
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K. Szocs, B. Lassegue, D. Sorescu, L. L. Hilenski, L. Valppu, T. L. Couse, J. N. Wilcox, M. T. Quinn, J.D. Lambeth, and K. K. Griendling Upregulation of Nox-Based NAD(P)H Oxidases in Restenosis After Carotid Injury Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 21 - 27. [Abstract] [Full Text] [PDF]
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 R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF]
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B. Fisslthaler, R. Popp, U. R. Michaelis, L. Kiss, I. Fleming, and R. Busse Cyclic Stretch Enhances the Expression and Activity of Coronary Endothelium-Derived Hyperpolarizing Factor Synthase Hypertension, December 1, 2001; 38(6): 1427 - 1432. [Abstract] [Full Text] [PDF]
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J.-M. Li and A. M. Shah Differential NADPH- versus NADH-dependent superoxide production by phagocyte-type endothelial cell NADPH oxidase Cardiovasc Res, December 1, 2001; 52(3): 477 - 486. [Abstract] [Full Text] [PDF]
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I. Fleming Cytochrome P450 and Vascular Homeostasis Circ. Res., October 26, 2001; 89(9): 753 - 762. [Abstract] [Full Text] [PDF]
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 A. H. WAGNER, M. R. SCHROETER, and M. HECKER 17{beta}-Estradiol inhibition of NADPH oxidase expression in human endothelial cells FASEB J, October 1, 2001; 15(12): 2121 - 2130. [Abstract] [Full Text] [PDF]
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 I. Fleming and R. Busse Vascular cytochrome P450 in the regulation of renal function and vascular tone: EDHF, superoxide anions and blood pressure Nephrol. Dial. Transplant., July 1, 2001; 16(7): 1309 - 1311. [Full Text] [PDF]
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W. B. Campbell and D. R. Harder Prologue: EDHF-what is it? Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2413 - H2416. [Full Text] [PDF]
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V. W. M. van Hinsbergh NO or H2O2 for Endothelium-Dependent Vasorelaxation : Tetrahydrobiopterin Makes the Difference Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 719 - 721. [Full Text] [PDF]
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R. Popp, R. P. Brandes, G. Ott, R. Busse, and I. Fleming Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid Circ. Res., April 19, 2002; 90(7): 800 - 806. [Abstract] [Full Text] [PDF]
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