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Research ArticleCardiovascular

Role of CYP1A1 in Modulating the Vascular and Blood Pressure Benefits of Omega-3 Polyunsaturated Fatty Acids

Larry N. Agbor, Elani F. Wiest, Michael Rothe, Wolf-Hagen Schunck and Mary K. Walker
Journal of Pharmacology and Experimental Therapeutics December 2014, 351 (3) 688-698; DOI: https://doi.org/10.1124/jpet.114.219535
Larry N. Agbor
Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico (L.N.A., E.F.W., M.K.W.); Lipidomix GmbH, Berlin, Germany (M.R.); and Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S.)
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Elani F. Wiest
Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico (L.N.A., E.F.W., M.K.W.); Lipidomix GmbH, Berlin, Germany (M.R.); and Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S.)
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Michael Rothe
Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico (L.N.A., E.F.W., M.K.W.); Lipidomix GmbH, Berlin, Germany (M.R.); and Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S.)
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Wolf-Hagen Schunck
Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico (L.N.A., E.F.W., M.K.W.); Lipidomix GmbH, Berlin, Germany (M.R.); and Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S.)
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Mary K. Walker
Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico (L.N.A., E.F.W., M.K.W.); Lipidomix GmbH, Berlin, Germany (M.R.); and Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S.)
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Abstract

The mechanisms that mediate the cardiovascular protective effects of omega 3 (n-3) polyunsaturated fatty acids (PUFAs) have not been fully elucidated. Cytochrome P450 1A1 efficiently metabolizes n-3 PUFAs to potent vasodilators. Thus, we hypothesized that dietary n-3 PUFAs increase nitric oxide (NO)–dependent blood pressure regulation and vasodilation in a CYP1A1-dependent manner. CYP1A1 wild-type (WT) and knockout (KO) mice were fed an n-3 or n-6 PUFA–enriched diet for 8 weeks and were analyzed for tissue fatty acids and metabolites, NO-dependent blood pressure regulation, NO-dependent vasodilation of acetylcholine (ACh) in mesenteric resistance arterioles, and endothelial NO synthase (eNOS) and phospho-Ser1177-eNOS expression in the aorta. All mice fed the n-3 PUFA diet showed significantly higher levels of n-3 PUFAs and their metabolites, and significantly lower levels of n-6 PUFAs and their metabolites. In addition, KO mice on the n-3 PUFA diet accumulated significantly higher levels of n-3 PUFAs in the aorta and kidney without a parallel increase in the levels of their metabolites. Moreover, KO mice exhibited significantly less NO-dependent regulation of blood pressure on the n-3 PUFA diet and significantly less NO-dependent, ACh-mediated vasodilation in mesenteric arterioles on both diets. Finally, the n-3 PUFA diet significantly increased aortic phospho-Ser1177-eNOS/eNOS ratio in the WT compared with KO mice. These data demonstrate that CYP1A1 contributes to eNOS activation, NO bioavailability, and NO-dependent blood pressure regulation mediated by dietary n-3 PUFAs.

Footnotes

    • Received August 22, 2014.
    • Accepted October 10, 2014.
  • ↵1 Current affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa.

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R21-HL107133]; and the National Institutes of Health National Institute of Environmental Health Sciences [Grant R15-ES021896].

  • dx.doi.org/10.1124/jpet.114.219535.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 3
1 Dec 2014
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Research ArticleCardiovascular

CYP1A1 and Cardiovascular Benefits of Omega-3 PUFAs

Larry N. Agbor, Elani F. Wiest, Michael Rothe, Wolf-Hagen Schunck and Mary K. Walker
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 688-698; DOI: https://doi.org/10.1124/jpet.114.219535

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Research ArticleCardiovascular

CYP1A1 and Cardiovascular Benefits of Omega-3 PUFAs

Larry N. Agbor, Elani F. Wiest, Michael Rothe, Wolf-Hagen Schunck and Mary K. Walker
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 688-698; DOI: https://doi.org/10.1124/jpet.114.219535
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