Soluble Epoxide Hydrolase Inhibition Exhibits Antihypertensive Actions Independently of Nitric Oxide in Mice with Renovascular Hypertension

Kopkan, Libor; Husková, Zuzana; Sporková, Alexandra; Varcabová, Šárka; Honetschlägerová, Zuzana; Hwang, Sung Hee; Tsai, Hui‐Jen; Hammock, Bruce D.; Imig, John D.; Kramer, Herbert J.; Bürgelová, Marcela; Vojtíšková, Alžběta; Kujal, Petr; Vernerová, Zdeňka; Červenka, Luděk

doi:10.1159/000339883

Cited by 24 publications

(44 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the subsequent measurement of the activity of sEH, the present study demonstrated for the first time, to the best of our knowledge, that the 20-HETE increased the protein activity of sEH in the liver and kidney of the hypertensive CYP4F2 transgenic mice. Consistently, previous studies have shown that the protein expression of sEH is upregulated in certain hypertensive models, including two-kidney-one-clip and angiotensin-II infusion hypertension (18)(19)(20), however, the mechanism remains to be elucidated. It has been reported that proinflammatory cytokines elevate the protein level of sEH (13).…”

Section: Discussionsupporting

confidence: 56%

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

Zhang

Lai

Liu

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Arachidonic acid (AA) can be metabolized into 20-hydroxyeicosatetraenoic acid (20-HETE) by ω-hydroxylases, and epoxyeicosatrienoic acids (EETs) by epoxygenases. The effects of EETs in cardiovascular physiology are vasodilatory, anti-inflammatory and anti-apoptotic, which are opposite to the function to 20-HETE. However, EETs are not stable in vivo, and are rapidly degraded to the biologically less active metabolites, dihydroxyeicosatrienoic acids, via soluble epoxide hydrolase (sEH). Western blotting, reverse transcription-quantitative polymerase chain reaction and liquid chromatography tandem mass spectrometry were performed in order to determine target RNA and protein expression levels. In the present study, it was demonstrated that the disturbed renal 20-HETE/EET ratio in the hypertensive cytochrome P450 4F2 transgenic mice was caused by the activation of sEH and the repression of epoxygenase activity. In addition, 20-HETE showed an opposite regulatory effect on the endogenous epoxygenases in the liver and kidney. Given that 20-HETE and EETs have opposite effects in multiple disease, the regulation of their formation and degradation may yield therapeutic benefits.

show abstract

Section: Discussionsupporting

confidence: 56%

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

Zhang

Lai

Liu

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…One group received TPPU alone (Ang II + TPPU animals) to control for the previously reported anti-hypertensive effects associated with sEHIs. 37, 38, 44 In order to provide evidence for sEH inhibition, we determined the TPPU concentration in blood samples that were collected at the end of each week after Ang II infusion. Even though we observed a mild accumulation of TPPU, the difference in TPPU levels on day 7 vs .…”

Section: Resultsmentioning

confidence: 99%

An Omega-3 Epoxide of Docosahexaenoic Acid Lowers Blood Pressure in Angiotensin-II–Dependent Hypertension

Ulu

Lee

Miyabe

et al. 2014

Journal of Cardiovascular Pharmacology

Self Cite

View full text Add to dashboard Cite

Mediators of anti-hypertensive actions of docosahexaenoic acid (DHA) are largely unknown. The omega-3 epoxide of DHA, 19, 20-EDP (epoxydocosapentaenoic acid) is metabolized by soluble epoxide hydrolase (sEH), which also metabolizes the anti-inflammatory and anti-hypertensive arachidonic acid (ARA) epoxides, EETs (epoxyeicosatrienoic acids). Based in part on plasma levels of EDPs following a DHA-rich diet, we hypothesized that 19, 20-EDP contributes to the anti-hypertensive actions of DHA in angiotensin-II dependent hypertension. Treatment individually with 19, 20-EDP, and a potent sEH inhibitor (sEHI) TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea) significantly lowered blood pressure (BP) as compared to angiotensin-II infused animals. The largest reduction in BP was obtained with the combination of 19, 20-EDP and TPPU, which was more efficacious than the combination of 14, 15-EET and TPPU. Oxylipin profiling revealed that 19, 20-EDP and 14, 15-EET infusion affected mostly metabolites of the P450 pathway but also renal levels of prostaglandin-E2. Our findings suggest that 19, 20- EDP is a mediator of the anti-hypertensive effects of DHA in angiotensin-II dependent hypertension. It appears that 19, 20- EDP requires metabolic stabilization with a sEHI to be most effective in lowering BP, although both TPPU and 19, 20- EDP are so effective on their own that demonstrating additive or synergistic interactions is difficult.

show abstract

“…For example, some oxylipins produced from arachidonic acid or linoleic acid have been associated with inflammation, [3][4][5] tissue damage, 6,7 vasoconstriction, 8,9 and oxidative stress. 10 In contrast, the epoxyeicosatrienoic acids (EETs) produced from arachidonic acid are endothelial-derived hyperpolarizing factors that are associated with vasodilation and natriuresis 11,12 and may indirectly propagate vasodilation [13][14][15] by activating endothelial nitric oxide synthase. 16,17 EETs can be rapidly metabolized to dihydroxyeicosatrienoic acids (DHETs) by the enzyme soluble epoxide hydrolase (sEH), resulting in a concomitant loss of vasodilation.…”

Section: July 2014mentioning

confidence: 99%

“…18,19 sEH also converts the protoxins, epoxyoctadecenoic acids, to the dihydroxyoctadecenoic acids, which are potent cytotoxic and proinflammatory metabolites. [20][21][22] Because products of sEH propagate loss of vascular relaxation and promote inflammation, targeting sEH inhibition pharmacologically has been used successfully to reduce blood pressure, 12,17,23 hypertension-associated renal damage, 17 and infarction size 23 in animal models. The proposed relationship between epoxygenase-derived oxylipins and hypertension is depicted in Figure 1.…”

Section: July 2014mentioning

confidence: 99%

See 1 more Smart Citation

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

et al. 2014

View full text Add to dashboard Cite

Abstract-In a randomized, double-blinded, controlled clinical trial, participants with peripheral arterial disease (75% hypertensive) consumed 30 g of milled flaxseed/d for 6 months. The flaxseed group exhibited significant reductions in systolic (−10 mm Hg) and diastolic (−7 mm Hg) blood pressure. Flaxseed contains the n3 fatty acid α-linolenic acid. Plasma α-linolenic acid increased with ingestion of flaxseed and was inversely associated with blood pressure. However, the antihypertensive mechanism was unclear. Oxylipins derived from polyunsaturated fatty acids regulate vascular tone. Therefore, the objective was to examine whether flaxseed consumption altered plasma oxylipins in a manner that influenced blood pressure. Plasma of FlaxPAD (Flaxseed for Peripheral Arterial Disease) participants underwent solid phase extraction and high-performance liquid chromatography-mass spectrometry/mass spectrometry analysis. The flaxseed group exhibited significant decreases in 8 plasma oxylipins versus control. Six of these (5,6-, 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acid and 9,10-and 12,13-dihydroxyoctadecenoic acid) were products of soluble epoxide hydrolase, a pharmacological target for antihypertensive treatment. Patients exhibiting a decrease in total plasma soluble epoxide hydrolase-derived oxylipins, exhibited a significant decrease in systolic blood pressure (mean [ and infarction size 23 in animal models. The proposed relationship between epoxygenase-derived oxylipins and hypertension is depicted in Figure 1.95%To test the hypothesis that flaxseed decreased the levels of oxylipins associated with inflammation and vasoconstriction, the study objectives were 3-fold: (1) to characterize and quantify the plasma oxylipin profile of participants with PAD, (2) to compare changes in plasma oxylipin concentrations in the control and flaxseed groups, and (3) to determine the mechanism whereby any changes in oxylipins may have influenced blood pressure in the FlaxPAD Trial. Methods Participants and Food ProductsA randomized, double-blinded, parallel, controlled clinical trial was established to determine the cardiovascular effects of dietary flaxseed in patients with PAD.24 Seventy-five percent of the participants were diagnosed as hypertensive at baseline (blood pressure ≥140/90 mm Hg).2,24 Participants (n=110) consumed food products containing either 30 g of milled flaxseed (treatment) or a combination of mixed dietary oils, milled wheat, and bran (control) for 6 months. Further details of the food product composition, 25,26 participant enrollment, intervention allocation, clinical characteristics, and blood pressure outcomes have been previously published.2,24 The trial is available at http://www.clinicaltrials.gov/ct2/show/NCT00781950?term=grant+p ierce+flax&rank=1.All participants provided informed consent, and all procedures were performed according to institutional guidelines. The trial was approved by Health Canada and its Natural Health Product Directorate, the University of Manitoba Research Ethics Board,...

show abstract

Soluble Epoxide Hydrolase Inhibition Exhibits Antihypertensive Actions Independently of Nitric Oxide in Mice with Renovascular Hypertension

Cited by 24 publications

References 66 publications

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

An Omega-3 Epoxide of Docosahexaenoic Acid Lowers Blood Pressure in Angiotensin-II–Dependent Hypertension

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

Contact Info

Product

Resources

About