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

Takashi Okada,Tomio Okamura,Satoshi Ugi,Katsutaro Morino,Keiko Kondo,Osamu Sekine,Masashi Tawa,Hiroshi Maegawa,Takeshi Imamura,Fumiyuki Nakagawa

doi:10.3390/nu9070654

Takashi Okada, Tomio Okamura + Show 8 more

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https://doi.org/10.3390/nu9070654

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Journal: Nutrients	Publication Date: Jun 24, 2017
Citations: 10	License type: CC BY 4.0

Affiliation: Shiga University of Medical Science

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.

Highlights

Endothelial dysfunction causes atherosclerosis and is induced by various factors including smoking, hypertension, dyslipidemia, and diabetes mellitus [1]
epoxyeicosatrienoic acids (EETs) are hydrolyzed to less active diols by the enzyme soluble epoxide hydrolase (sEH). sEH protein expression in rat aortic strips was lower in the fish oil-fed group than in the control group (Figure 1B)
We have previously reported the protective effect of 4-hydroxy hexenal (4-HHE) on the endothelium via nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor for antioxidants and oxidative stress [16]

Summary

Introduction

Endothelial dysfunction causes atherosclerosis and is induced by various factors including smoking, hypertension, dyslipidemia, and diabetes mellitus [1]. Nitric oxide (NO), which is generated by endothelial NO synthase (eNOS), is a major modulator in acetylcholine-induced vasodilation and reactive hyperemia [2]. Recent studies have revealed that in arteries from a variety of species, including humans, epoxyeicosatrienoic acids (EETs) act as EDHFs [4,5]. The endothelium expresses soluble epoxide hydrolase (sEH), which rapidly hydrolyzes EETs to dihydroxyeicosatrienoic acids (DHETs) [6]. Both the potentiation of vascular EET synthesis and the reduction in EET hydrolysis increase EET bioavailability, which results in decreased vascular tone

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