Document Detail


Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega-3 polyunsaturated fatty acids.
MedLine Citation:
PMID:  22995157     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega-3 polyunsaturated fatty acids (n-3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n-3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice±NO synthase (NOS) inhibitor. We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA±inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mmHg, WT 103±1, KO 116±1, n=5/genotype, p<0.05), and exhibited a reduced heart rate (beats per minute, WT 575±5; KO 530±7; p<0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n-3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP.
Authors:
Larry N Agbor; Mary T Walsh; Jason R Boberg; Mary K Walker
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-18
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  264     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-22     Completed Date:  2012-12-28     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  351-60     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aorta / metabolism
Blood Pressure / drug effects*,  genetics
Cytochrome P-450 CYP1A1 / genetics,  metabolism*
Fatty Acids, Omega-3 / pharmacology*
Gene Expression Regulation
Genetic Predisposition to Disease
Heart Rate
Mesentery / blood supply
Mice
Mice, Knockout
Nitric Oxide Synthase / genetics,  metabolism
Nitrogen Oxides
Vasodilation / drug effects*
Grant Support
ID/Acronym/Agency:
R21 HL107133/HL/NHLBI NIH HHS; R21 HL107133/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids, Omega-3; 0/Nitrogen Oxides; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.14.1/Cytochrome P-450 CYP1A1
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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