title: Role of CYP1A1 in modulating the vascular and blood pressure benefits of omega-3 polyunsaturated fatty acids.
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.
authors.affiliation: 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.).
authors.forename: Larry N
authors.initials: LN
authors.lastname: Agbor
authors.affiliation: 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.).
authors.forename: Elani F
authors.initials: EF
authors.lastname: Wiest
authors.affiliation: 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.).
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.affiliation: 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.).
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
authors.affiliation: 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.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Walker
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology*; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*
chemical_list: D015525:Fatty Acids, Omega-3; D009569:Nitric Oxide; D019363:Cytochrome P-450 CYP1A1