Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor γ Agonists/Soluble Epoxide Hydrolase Inhibitors

The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH+/+, sEH−/− mice showed enhanced CRH, including greater repayment volume (RV; 28% higher, P < 0.001) and repayment/debt ratio (32% higher, P < 0.001). Oxylipins from the heart perfusates were analyzed by LC-MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline ( P < 0.001) and 5.6-fold higher post-ischemia ( P < 0.001) in sEH−/− compared with sEH+/+ mice. Likewise, the baseline 9,10- and 12,13-EpOME/DiHOME ratios were 3.2-fold ( P < 0.01) and 3.7-fold ( P < 0.001) higher, respectively in sEH−/− compared with sEH+/+ mice. 13-HODE was also significantly increased at baseline by 71% ( P < 0.01) in sEH−/− vs. sEH+/+ mice. Levels of 5-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids were not significantly different between the two strains ( P > 0.05), but were decreased postischemia in both groups ( P = 0.02, P = 0.04, P = 0.05, P = 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPARγ) was demonstrated using a PPARγ-antagonist (T0070907), which reduced repayment volume by 25% in sEH+/+ ( P < 0.001) and 33% in sEH−/− mice ( P < 0.01), and a PPARγ-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH+/+ ( P = 0.04) and sEH−/− mice ( P = 0.04). l-NAME attenuated CRH in both sEH−/− and sEH+/+. These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response.

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Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ

Frontiers in Pharmacology ◽

10.3389/fphar.2019.00263 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 4

Author(s):

Tamara Göbel ◽

Olaf Diehl ◽

Jan Heering ◽

Daniel Merk ◽

Carlo Angioni ◽

...

Keyword(s):

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

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Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing β-oxidation of fatty acid in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00148.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. G527-G538 ◽

Cited By ~ 10

Author(s):

Liu Yao ◽

Boyang Cao ◽

Qian Cheng ◽

Wenbin Cai ◽

Chenji Ye ◽

...

Keyword(s):

Fatty Acids ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Nonalcoholic Fatty Liver

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg−1·day−1 for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated β-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.

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Design and synthesis of fused soluble epoxide hydrolase/peroxisome proliferator-activated receptor modulators

MedChemComm ◽

10.1039/c6md00042h ◽

2016 ◽

Vol 7 (6) ◽

pp. 1209-1216 ◽

Cited By ~ 4

Author(s):

R. Blöcher ◽

C. Lamers ◽

S. K. Wittmann ◽

O. Diehl ◽

T. Hanke ◽

...

Keyword(s):

Type Ii Diabetes ◽

Epoxide Hydrolase ◽

Complex Disease ◽

Soluble Epoxide Hydrolase ◽

Peroxisome Proliferator ◽

Type Ii ◽

Peroxisome Proliferator Activated Receptor ◽

Design And Synthesis ◽

Disease Cluster ◽

Receptor Modulators

Metabolic syndrome (MetS) is a widespread, complex disease cluster which consists of hypertension, atherosclerosis, dyslipidaemia and type II diabetes.

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Action of epoxyeicosatrienoic acids on cellular function

AJP Cell Physiology ◽

10.1152/ajpcell.00402.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. C996-C1012 ◽

Cited By ~ 310

Author(s):

Arthur A. Spector ◽

Andrew W. Norris

Keyword(s):

Epoxide Hydrolase ◽

Direct Interaction ◽

Soluble Epoxide Hydrolase ◽

Epoxyeicosatrienoic Acids ◽

Peroxisome Proliferator ◽

Potential Therapeutic Target ◽

Peroxisome Proliferator Activated Receptor ◽

Effector System ◽

Modulation Of Gene Expression ◽

Cytochrome P 450

Epoxyeicosatrienoic acids (EETs), which function primarily as autocrine and paracrine mediators in the cardiovascular and renal systems, are synthesized from arachidonic acid by cytochrome P-450 epoxygenases. They activate smooth muscle large-conductance Ca2+-activated K+ channels, producing hyperpolarization and vasorelaxation. EETs also have anti-inflammatory effects in the vasculature and kidney, stimulate angiogenesis, and have mitogenic effects in the kidney. Many of the functional effects of EETs occur through activation of signal transduction pathways and modulation of gene expression, events probably initiated by binding to a putative cell surface EET receptor. However, EETs are rapidly taken up by cells and are incorporated into and released from phospholipids, suggesting that some functional effects may occur through a direct interaction between the EET and an intracellular effector system. In this regard, EETs and several of their metabolites activate peroxisome proliferator-activated receptor α (PPARα) and PPARγ, suggesting that some functional effects may result from PPAR activation. EETs are metabolized primarily by conversion to dihydroxyeicosatrienoic acids (DHETs), a reaction catalyzed by soluble epoxide hydrolase (sEH). Many potentially beneficial actions of EETs are attenuated upon conversion to DHETs, which do not appear to be essential under routine conditions. Therefore, sEH is considered a potential therapeutic target for enhancing the beneficial functions of EETs.

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