Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs)

Previous studies suggest that epoxyeicosatrienoic acids (EETs) are vasodilators of the mesenteric artery; however, the production and regulation of EETs in the mesenteric artery remain unclear. The present study was designed 1) to determine which epoxygenase isoform may contribute to formation of EETs in mesenteric arteries and 2) to determine the regulation of mesenteric artery cytochrome P-450 (CYP) enzymes in obese Zucker rats. Microvessels were incubated with arachidonic acid, and CYP enzyme activity was determined. Mesenteric arteries demonstrate detectable epoxygenase and hydroxylase activities. Next, protein and mRNA expressions were determined in microvessels. Although renal microvessels express CYP2C23 mRNA and protein, mesenteric arteries lacked CYP2C23 expression. CYP2C11 and CYP2J mRNA and protein were expressed in mesenteric arteries and renal microvessels. In addition, mesenteric artery protein expression was evaluated in lean and obese Zucker rats. Compared with lean Zucker rats, mesenteric arterial CYP2C11 and CYP2J proteins were decreased by 38 and 43%, respectively, in obese Zucker rats. In contrast, soluble epoxide hydrolase mRNA and protein expressions were significantly increased in obese Zucker rat mesenteric arteries. In addition, nitric oxide-independent dilation evoked by acetylcholine was significantly attenuated in mesenteric arteries of obese Zucker rats. These data suggest that the main epoxygenase isoforms expressed in mesenteric arteries are different from those expressed in renal microvessels and that decreased epoxygenases and increased soluble epoxide hydrolase are associated with impaired mesenteric artery dilator function in obese Zucker rats.

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Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

Molecules ◽

10.3390/molecules25235488 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5488

Author(s):

Amarjyoti Das Mahapatra ◽

Rinku Choubey ◽

Bhaskar Datta

Keyword(s):

Small Molecule ◽

Combination Chemotherapy ◽

Epoxide Hydrolase ◽

Therapeutic Strategy ◽

Soluble Epoxide Hydrolase ◽

Epoxyeicosatrienoic Acids ◽

Protective Properties ◽

Soluble Epoxide Hydrolase Inhibitors ◽

Synthetic Scaffolds ◽

Structural Insights

The enzyme soluble epoxide hydrolase (sEH) plays a central role in metabolism of bioactive lipid signaling molecules. The substrate-specific hydrolase activity of sEH converts epoxyeicosatrienoic acids (EETs) to less bioactive dihydroxyeicosatrienoic acids. EETs exhibit anti-inflammatory, analgesic, antihypertensive, cardio-protective and organ-protective properties. Accordingly, sEH inhibition is a promising therapeutic strategy for addressing a variety of diseases. In this review, we describe small molecule architectures that have been commonly deployed as sEH inhibitors with respect to angiogenesis, inflammation and cancer. We juxtapose commonly used synthetic scaffolds and natural products within the paradigm of a multitarget approach for addressing inflammation and inflammation induced carcinogenesis. Structural insights from the inhibitor complexes and novel strategies for development of sEH-based multitarget inhibitors are also presented. While sEH inhibition is likely to suppress inflammation-induced carcinogenesis, it can also lead to enhanced angiogenesis via increased EET concentrations. In this regard, sEH inhibitors in combination chemotherapy are described. Urea and amide-based architectures feature prominently across multitarget inhibition and combination chemotherapy applications of sEH inhibitors.

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Epoxyeicosatrienoic acids and the soluble epoxide hydrolase are determinants of pulmonary artery pressure and the acute hypoxic pulmonary vasoconstrictor response

The FASEB Journal ◽

10.1096/fj.08-112821 ◽

2008 ◽

Vol 22 (12) ◽

pp. 4306-4315 ◽

Cited By ~ 84

Author(s):

Benjamin Keserü ◽

Eduardo Barbosa‐Sicard ◽

Rüdiger Popp ◽

Beate Fisslthaler ◽

Alexander Dietrich ◽

...

Keyword(s):

Pulmonary Artery ◽

Pulmonary Artery Pressure ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Epoxyeicosatrienoic Acids ◽

Artery Pressure ◽

Vasoconstrictor Response

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Pinocembrin protects rats against cerebral ischemic damage through soluble epoxide hydrolase and epoxyeicosatrienoic acids

Chinese Journal of Natural Medicines ◽

10.1016/s1875-5364(13)60018-7 ◽

2013 ◽

Vol 11 (3) ◽

pp. 207-213 ◽

Cited By ~ 2

Author(s):

Shou-Bao WANG ◽

Xiao-Bin PANG ◽

Mei GAO ◽

Lian-Hua FANG ◽

Guan-Hua DU

Keyword(s):

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Epoxyeicosatrienoic Acids ◽

Ischemic Damage ◽

Cerebral Ischemic ◽

Cerebral Ischemic Damage

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Inhibition of soluble epoxide hydrolase attenuates a high-fat diet-mediated renal injury by activating PAX2 and AMPK

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1815746116 ◽

2019 ◽

Vol 116 (11) ◽

pp. 5154-5159 ◽

Cited By ~ 10

Author(s):

Ying Luo ◽

Ming-Yu Wu ◽

Bing-Qing Deng ◽

Jian Huang ◽

Sung Hee Hwang ◽

...

Keyword(s):

Renal Injury ◽

High Fat Diet ◽

Epoxide Hydrolase ◽

Mesangial Cells ◽

Soluble Epoxide Hydrolase ◽

Epoxyeicosatrienoic Acids ◽

High Fat ◽

Plasmid Construction ◽

Protein Levels ◽

Chaperone Mediated Autophagy

A high-fat diet (HFD) causes obesity-associated morbidities involved in macroautophagy and chaperone-mediated autophagy (CMA). AMPK, the mediator of macroautophage, has been reported to be inactivated in HFD-caused renal injury. However, PAX2, the mediator for CMA, has not been reported in HFD-caused renal injury. Here we report that HFD-caused renal injury involved the inactivation of Pax2 and Ampk, and the activation of soluble epoxide hydrolase (sEH), in a murine model. Specifically, mice fed on an HFD for 2, 4, and 8 wk showed time-dependent renal injury, the significant decrease in renal Pax2 and Ampk at both mRNA and protein levels, and a significant increase in renal sEH at mRNA, protein, and molecular levels. Also, administration of an sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea, significantly attenuated the HFD-caused renal injury, decreased renal sEH consistently at mRNA and protein levels, modified the renal levels of sEH-mediated epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) as expected, and increased renal Pax2 and Ampk at mRNA and/or protein levels. Furthermore, palmitic acid (PA) treatment caused significant increase in Mcp-1, and decrease in both Pax2 and Ampk in murine renal mesangial cells (mRMCs) time- and dose-dependently. Also, 14(15)-EET (a major substrate of sEH), but not its sEH-mediated metabolite 14,15-DHET, significantly reversed PA-induced increase in Mcp-1, and PA-induced decrease in Pax2 and Ampk. In addition, plasmid construction revealed that Pax2 may positively regulate Ampk transcriptionally in mRMCs. This study provides insights into and therapeutic target for the HFD-mediated renal injury.

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