scholarly journals Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BKCa channels: implications for soluble epoxide hydrolase inhibition

2006 ◽  
Vol 290 (2) ◽  
pp. H491-H499 ◽  
Author(s):  
Brandon T. Larsen ◽  
Hiroto Miura ◽  
Ossama A. Hatoum ◽  
William B. Campbell ◽  
Bruce D. Hammock ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Right Atrial ◽  
Epoxyeicosatrienoic Acids ◽  
Ionization Mass ◽  
Vasomotor Tone ◽  
Bkca Channels ◽  
Endothelial Denudation ◽  
Cytochrome P 450 ◽  
Coronary Arterioles

Epoxyeicosatrienoic acids (EETs) are metabolized by soluble epoxide hydrolase (sEH) to form dihydroxyeicosatrienoic acids (DHETs) and are putative endothelium-derived hyperpolarizing factors (EDHFs). EDHFs modulate microvascular tone; however, the chemical identity of EDHF in the human coronary microcirculation is not known. We examined the capacity of EETs, DHETs, and sEH inhibition to affect vasomotor tone in isolated human coronary arterioles (HCAs). HCAs from right atrial appendages were prepared for videomicroscopy and immunohistochemistry. In vessels preconstricted with endothelin-1, three EET regioisomers (8,9-, 11,12-, and 14,15-EET) each induced a concentration-dependent dilation that was sensitive to blockade of large-conductance Ca2+-activated K+ (BKCa) channels by iberiotoxin. EET-induced dilation was not altered by endothelial denudation. 8,9-, 11,12-, and 14,15-DHET also dilated HCA via activation of BKCa channels. Dilation was less with 8,9- and 14,15-DHET but was similar with 11,12-DHET, compared with the corresponding EETs. Immunohistochemistry revealed prominent expression of cytochrome P-450 (CYP450) 2C8, 2C9, and 2J2, enzymes that may produce EETs, as well as sEH, in HCA. Inhibition of sEH by 1-cyclohexyl-3-dodecylurea (CDU) enhanced dilation caused by 14,15-EET but reduced dilation observed with 11,12-EET. DHET production from exogenous EETs was reduced in vessels pretreated with CDU compared with control, as measured by liquid chromatography electrospray-ionization mass spectrometry. In conclusion, EETs and DHETs dilate HCA by activating BKCa channels, supporting a role for EETs/DHETs as EDHFs in the human heart. CYP450s and sEH may be endogenous sources of these compounds, and sEH inhibition has the potential to alter myocardial perfusion, depending on which EETs are produced endogenously.

Decreased epoxygenase and increased epoxide hydrolase expression in the mesenteric artery of obese Zucker rats

2005 ◽  
Vol 288 (1) ◽  
pp. R188-R196 ◽  
Author(s):  
Xueying Zhao ◽  
Aparajita Dey ◽  
Olga P. Romanko ◽  
David W. Stepp ◽  
Mong-Heng Wang ◽  
...  
Keyword(s):  
Mesenteric Artery ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Mesenteric Arteries ◽  
Zucker Rats ◽  
Epoxyeicosatrienoic Acids ◽  
Obese Zucker Rat ◽  
Protein Expressions ◽  
Obese Zucker Rats ◽  
Cytochrome P 450

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.

Action of epoxyeicosatrienoic acids on cellular function

2007 ◽  
Vol 292 (3) ◽  
pp. C996-C1012 ◽  
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.

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

Molecules ◽  
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.

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

2008 ◽  
Vol 22 (12) ◽  
pp. 4306-4315 ◽  
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

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

2007 ◽  
Vol 82 (1-4) ◽  
pp. 42-49 ◽  
Author(s):  
Bora Inceoglu ◽  
Kara R. Schmelzer ◽  
Christophe Morisseau ◽  
Steve L. Jinks ◽  
Bruce D. Hammock
Keyword(s):  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Epoxyeicosatrienoic Acids ◽  
Biological Functions

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

2019 ◽  
Vol 116 (11) ◽  
pp. 5154-5159 ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document