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J Pharmacol Exp Ther. 2014 Dec;351(3):688-98. doi: 10.1124/jpet.114.219535. Epub 2014 Oct 14.

Role of CYP1A1 in modulating the vascular and blood pressure benefits of omega-3 polyunsaturated fatty acids.

Author information

1
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.).
2
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.) mwalker@salud.unm.edu.

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.

PMID:
25316121
PMCID:
PMC4244579
DOI:
10.1124/jpet.114.219535
[Indexed for MEDLINE]
Free PMC Article

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