Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease

Abstract Introduction In search for new therapeutic measures of congestive heart failure (CHF) attention focused on the role of epoxyeicosatrienoic acids (EETs), cytochrome P450-dependent epoxygenase pathway metabolites of arachidonic acid, with antihypertensive and organ-protective actions. The EETs are rapidly broken-down by soluble epoxide hydrolase (sEH). Blocking sEH and increasing tissue EETs bioavailability had antihypertensive and cardio- and renoprotective effects. The studies of the biological mechanisms underlying the sex-related differences in the CHF and in the responses to new pharmacological measures are missing. The rat model in which CHF is induced by volume overload by creation of the aorto-caval fistula (ACF) is recommended for preclinical studies by American Heart Association. It has been noticed that the hypertensive rat transgenic for the mouse Ren-2 renin gene (TGR) presents a unique angiotensin II-dependent model of hypertension. We found that male ACF TGR displayed tissue deficiency of EETs, and increasing intrarenal EETs levels by pharmacological blockade of sEH attenuated the progression of CHF in male ACF TGR. However, we did not examine if this effect occurs also in female ACF TGR. Purpose The aim was to establish if sex-related differences, if present, are demonstrable with standard treatment with ACEi alone and with the combined treatment with ACEi and sEHi. Methods Male and female TGR rats were randomly assigned either to ACF procedure or to sham-operation. One week after the procedure rats were divided into the 8 experimental groups (sham-operated male TGR + placebo, ACF male TGR + placebo, ACF male TGR + ACEi, ACF male TGR + ACEi + sEHi, sham-operated female TGR + placebo, ACF female TGR + placebo, ACF female TGR + ACEi, ACF female TGR + ACEi + sEHi). C-AUCB was used as an sEHi and trandolapril as ACEi, both in drinking water in doses previously tested. The follow-up period was 50 weeks and the primary end-point was death from any cause. Results All sham-operated male and female TGR survived until the end of experiment. All untreated male ACF TGR animals died by week 20. In contrast, untreated female ACF survived in the rate of 32%. The treatment with ACEi improved survival rate similary in male as well as female ACF TGR (74% and 65%). The combined treatment with ACEi and sEHi worsened the survival in male ACF TGR as compared with ACF TGR + ACEi (38%). In contrast, the combined treatment with ACEi and sEHi in female ACF TGR significantly improved the course and the final survival rate (84%) as compared with female ACF TGR + ACEi alone. Picture 1 Conclusions The study suggests that in CHF individuals in whom hypertension and increased RAS activity run in parallel, the patients' sex is the co-determinant of CHF progression. In particular it can influence the effectiveness of the therapeutic measures applied to slow it down. Therefore, in pre- and clinical studies the sex-related differences should be seriously considered. Acknowledgement/Funding Ministry of Health of the Czech Republic grant no. 17- 28220A; Grant Agency of Charles University, project number 32218

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Inhibition of soluble epoxide hydrolase regulates monocyte/macrophage polarization and improves neurological outcome in a rat model of ischemic stroke

Neuroreport ◽

10.1097/wnr.0000000000001248 ◽

2019 ◽

Vol 30 (8) ◽

pp. 567-572 ◽

Cited By ~ 7

Author(s):

Chien-Fu Yeh ◽

Tung-Yueh Chuang ◽

Yu-Wen Hung ◽

Ming-Ying Lan ◽

Ching-Han Tsai ◽

...

Keyword(s):

Ischemic Stroke ◽

Rat Model ◽

Neurological Outcome ◽

Epoxide Hydrolase ◽

Macrophage Polarization ◽

Soluble Epoxide Hydrolase

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Anti-inflammatory treatment with a soluble epoxide hydrolase inhibitor attenuates seizures and epilepsy-associated depression in the LiCl-pilocarpine post-status epilepticus rat model

Brain Behavior and Immunity ◽

10.1016/j.bbi.2019.07.014 ◽

2019 ◽

Vol 81 ◽

pp. 535-544 ◽

Cited By ~ 3

Author(s):

Yijun Shen ◽

Weifeng Peng ◽

Qinglan Chen ◽

Bruce D Hammock ◽

Junyan Liu ◽

...

Keyword(s):

Status Epilepticus ◽

Rat Model ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase Inhibitor ◽

Anti Inflammatory

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Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain

Life Sciences ◽

10.1016/j.lfs.2006.07.031 ◽

2006 ◽

Vol 79 (24) ◽

pp. 2311-2319 ◽

Cited By ~ 104

Author(s):

Bora Inceoglu ◽

Steven L. Jinks ◽

Kara R. Schmelzer ◽

Troy Waite ◽

In Hae Kim ◽

...

Keyword(s):

Rat Model ◽

Inflammatory Pain ◽

Mechanical Allodynia ◽

Epoxide Hydrolase ◽

Thermal Hyperalgesia ◽

Soluble Epoxide Hydrolase

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Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2011.11.015 ◽

2012 ◽

Vol 52 (3) ◽

pp. 660-666 ◽

Cited By ~ 41

Author(s):

Nassiba Merabet ◽

Jeremy Bellien ◽

Etienne Glevarec ◽

Lionel Nicol ◽

Daniele Lucas ◽

...

Keyword(s):

Heart Failure ◽

Myocardial Perfusion ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Experimental Heart Failure ◽

And Function

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Inhibiting the soluble epoxide hydrolase increases the EpFAs and ERK1/2 expression in the hippocampus of LiCl-pilocarpine post-status epilepticus rat model

10.21203/rs.3.rs-385335/v1 ◽

2021 ◽

Author(s):

Weifeng Peng ◽

Yijun Shen ◽

Qiang Wang ◽

Jing Ding ◽

Xin Wang

Keyword(s):

Fatty Acids ◽

Enzyme Activity ◽

Status Epilepticus ◽

Rat Model ◽

Protein Level ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Peg 400

Abstract Purpose This study aimed to investigate the enzyme activity of soluble epoxide hydrolase (sEH) and quantify metabolic substrates i.e. epoxygenated fatty acids (EpFAs) and products of sEH in the hippocampus after administering TPPU [1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea], the inhibitor of sEH, and further explored whether the extracellular signal-activated protein kinase 1/2 (ERK1/2) was involved in the anti-seizure effect of TPPU in the lithium chloride (LiCl)-pilocarpine induced post-status epilepticus (SE) rat model. Methods The rats were intraperitoneally (I.P.) injected with LiCl and pilocarpine to induce SE and then spontaneous recurrent seizures (SRS) were observed. Rats were randomly assigned into SRS + 0.1 TPPU group (intragastrically administering 0.1 mg/kg/d TPPU), SRS + PEG 400 group (administering the vehicle instead), and Control group. Enzyme-linked immunosorbent assay, Western-blot analysis, and ultra-high-performance liquid chromatography/mass spectrometry (LC/MS) were performed to measure the enzyme activity of sEH, the protein level of sEH and ERK1/2, and the concentration of TPPU and polyunsaturated fatty acids (PUFAs) metabolisms in the hippocampus. Results The frequency of SRS that equal to or greater than Racine 3 degree ranged from 0 to 19 every week in the SRS + PEG 400 group comparing to 0 to 5 every week in the SRS + 0.1 TPPU group. The enzyme activity and protein level of sEH was significantly increased in the SRS + PEG400 group compared with the Control group. After administering TPPU, the concentration of TPPU in the hippocampus was 10.94 ± 4.37 nmol/kg; the enzyme level of sEH was significantly decreased in the LiCl-pilocarpine-induced post-SE rat model, however, the protein level of sEH did not decrease significantly; the regioisomers 8,9-, 11,12-, and 14,15-EETs, the sums of EETs, the ratio of EETs/DHETs, and other EpFAs including 16(17) EpDPA and the ratio of 19(20)-EpDPA/19,20-DiHDPA in the hippocampus were significantly increased. In addition, the ratio of p-ERK1/2 to ERK1/2 in the hippocampus was significantly increased after TPPU administration either. Conclusion We demonstrated that inhibiting sEH with TPPU increased the levels of EETs and some other EpFAs and expression of ERK1/2 in the hippocampus of LiCl-pilocarpine-induced post-SE rat model, indicating the cellular mechanism of EETs through ERK1/2 pathway might be responsible for the anti-seizure effect of TPPU.

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Effect of Angiotensin-Converting Enzyme Blockade, Alone or Combined With Blockade of Soluble Epoxide Hydrolase, on the Course of Congestive Heart Failure and Occurrence of Renal Dysfunction in Ren-2 Transgenic Hypertensive Rats With Aorto-Caval Fistula

Physiological Research ◽

10.33549/physiolres.933757 ◽

2017 ◽

pp. 401-415 ◽

Cited By ~ 3

Author(s):

P. KALA ◽

L. SEDLÁKOVÁ ◽

P. ŠKAROUPKOVÁ ◽

L. KOPKAN ◽

Z. VAŇOURKOVÁ ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Survival Rate ◽

Angiotensin Converting Enzyme ◽

Renal Dysfunction ◽

Epoxide Hydrolase ◽

Combined Treatment ◽

Soluble Epoxide Hydrolase ◽

Converting Enzyme ◽

Hypertensive Rats

We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.

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