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Title: Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids

Abstract

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 mm Hg, 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 KOmore » 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. -- Highlights: ► CYP1A1 KO mice are hypertensive. ► CYP1A1 KO mice exhibit reduced vasodilation responses to n-3 PUFAs. ► Constitutive CYP1A1 expression regulates blood pressure and vascular function.« less

Authors:
; ; ;
Publication Date:
OSTI Identifier:
22215955
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 264; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETYLCHOLINE; AORTA; ARGININE; BLOOD PRESSURE; DBP; HEART; HYPERTENSION; KNOCK-OUT REACTIONS; METABOLITES; MICE; NITRATES; NITRIC OXIDE; NITRITES; PENICILLAMINE; POTASSIUM; US EPA; VASODILATION; VASODILATORS

Citation Formats

Agbor, Larry N., Walsh, Mary T., Boberg, Jason R., and Walker, Mary K., E-mail: mwalker@salud.unm.edu. Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.09.007.
Agbor, Larry N., Walsh, Mary T., Boberg, Jason R., & Walker, Mary K., E-mail: mwalker@salud.unm.edu. Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids. United States. doi:10.1016/J.TAAP.2012.09.007.
Agbor, Larry N., Walsh, Mary T., Boberg, Jason R., and Walker, Mary K., E-mail: mwalker@salud.unm.edu. Thu . "Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids". United States. doi:10.1016/J.TAAP.2012.09.007.
@article{osti_22215955,
title = {Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids},
author = {Agbor, Larry N. and Walsh, Mary T. and Boberg, Jason R. and Walker, Mary K., E-mail: mwalker@salud.unm.edu},
abstractNote = {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 mm Hg, 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. -- Highlights: ► CYP1A1 KO mice are hypertensive. ► CYP1A1 KO mice exhibit reduced vasodilation responses to n-3 PUFAs. ► Constitutive CYP1A1 expression regulates blood pressure and vascular function.},
doi = {10.1016/J.TAAP.2012.09.007},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 264,
place = {United States},
year = {2012},
month = {11}
}