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Nutrients. 2017 Jun 24;9(7). pii: E654. doi: 10.3390/nu9070654.

N-3 Polyunsaturated Fatty Acids Decrease the Protein Expression of Soluble Epoxide Hydrolase via Oxidative Stress-Induced P38 Kinase in Rat Endothelial Cells.

Author information

1
Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. tokada@belle.shiga-med.ac.jp.
2
Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. morino@belle.shiga-med.ac.jp.
3
Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. fumiyuki-nakagawa@cmicgroup.com.
4
Nishiwaki Laboratory, CMIC Biopharma Co., Ltd., Hyogo 677-0032, Japan. fumiyuki-nakagawa@cmicgroup.com.
5
Department of Pharmacology, Shiga University of Medical Science, Shiga 520-2192, Japan. tawa@belle.shiga-med.ac.jp.
6
Department of Public Health, Shiga University of Medical Science, Shiga 520-2192, Japan. kon@belle.shiga-med.ac.jp.
7
Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. sekine@belle.shiga-med.ac.jp.
8
Department of Pharmacology, Shiga University of Medical Science, Shiga 520-2192, Japan. timamura@med.tottori-u.ac.jp.
9
Division of Molecular Pharmacology, Department of Medicine, Tottori University, Tottori 683-8503, Japan. timamura@med.tottori-u.ac.jp.
10
Department of Pharmacology, Shiga University of Medical Science, Shiga 520-2192, Japan. okamura@belle.shiga-med.ac.jp.
11
Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. sugi@belle.shiga-med.ac.jp.
12
Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. maegawa@belle.shiga-med.ac.jp.

Abstract

N-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels. Sprague-Dawley rats were fed either a control or fish oil diet for 3 weeks. Compared with the control, the fish oil diet improved acetylcholine-induced vasodilation and reduced the protein expression of soluble epoxide hydrolase (sEH), a key EET metabolic enzyme, in aortic strips. Both DHA and EPA suppressed sEH protein expression in rat aorta endothelial cells (RAECs). Furthermore, the concentration of 4-hydroxy hexenal (4-HHE), a lipid peroxidation product of n-3 PUFAs, increased in n-3 PUFA-treated RAECs. In addition, 4-HHE treatment suppressed sEH expression in RAECs, suggesting that 4-HHE (derived from n-3 PUFAs) is involved in this phenomenon. The suppression of sEH was attenuated by the p38 kinase inhibitor (SB203580) and by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, sEH expression decreased after n-3 PUFAs treatment, potentially through oxidative stress and p38 kinase. Mild oxidative stress induced by n-3 PUFAs may contribute to their cardio-protective effect.

KEYWORDS:

endothelial function; epoxyeicosatrienoic acid; n-3 PUFA; p38 kinase; soluble epoxide hydrolase

PMID:
28672788
PMCID:
PMC5537774
DOI:
10.3390/nu9070654
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

This study was performed by Shiga University of Medical Science in collaboration with CMIC Pharma Science. F.N. is an employee of CMIC Pharma Science Corporation and a graduate student at Shiga University of Medical Science. Shiga University of Medical Science receives grants from Mochida and Takeda. However, the research topics of these grants are not restricted. The founding sponsors had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

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