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Cytochrome P450 2C is an EDHF synthase in coronary arteries

Nature volume 401, pages 493–497 (1999)Cite this article

Abstract

In most arterial beds a significant endothelium-dependent dilation to various stimuli persists even after inhibition of nitric oxide synthase and cyclo-oxygenase. This dilator response is preceded by an endothelium-dependent hyperpolarization of vascular smooth muscle cells, which is sensitive to a combination of the calcium-dependent potassium-channel inhibitors charybdotoxin and apamin, and is assumed to be mediated by an unidentified endothelium-derived hyperpolarizing factor (EDHF)1,2. Here we show that the induction of cytochrome P450 (CYP) 2C8/34 in native porcine coronary artery endothelial cells by β-naphthoflavone enhances the formation of 11,12-epoxyeicosatrienoic acid, as well as EDHF-mediated hyperpolarization and relaxation. Transfection of coronary arteries with CYP 2C8/34 antisense oligonucleotides results in decreased levels of CYP 2C and attenuates EDHF-mediated vascular responses. Thus, a CYP-epoxygenase product is an essential component of EDHF-mediated relaxation in the porcine coronary artery, and CYP 2C8/34 fulfils the criteria for the coronary EDHF synthase.

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Figure 1: Increased expression of CYP 2C enhances EDHF-mediated relaxation of PCA and generation of 11,12-EET.
Figure 2: Increased expression of CYP 2C enhances, and sulphaphenazole inhibits, the EDHF-mediated hyperpolarization of PCA.
Figure 3: CYP 2C8/34 antisense oligonucleotides attenuate the expression of CYP 2C protein and the EDHF-mediated relaxation of PCA.
Figure 4: CYP 2C antisense oligonucleotides abolish bradykinin-induced, EDHF-mediated hyperpolarization of PCA smooth muscle cells.

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Acknowledgements

We thank I. Winter, M. Stächele, N. Hinsch and S. Hauk for expert technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft and Institut de Recherches Internationales Servier.

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Authors and Affiliations

  1. Institut für Kardiovaskuläre Physiologie, Klinikum der J. W. Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, D-60590, Germany

    Beate Fisslthaler, Rüdiger Popp, Michael Potente, Ingrid Fleming & Rudi Busse

  2. Zentrum der Inneren Medizin, Justus Liebig Universität Gießen, Klinikstrasse 36, Gießen, D-35392, Germany

    Ladislau Kiss

  3. Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, 53226, Wisconsin, USA

    David R. Harder

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  1. Beate Fisslthaler
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Correspondence to Ingrid Fleming.

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Fisslthaler, B., Popp, R., Kiss, L. et al. Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 401, 493–497 (1999). https://doi.org/10.1038/46816

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