Soluble Epoxide Hydrolase Activity Determines the Severity of Ischemia-Reperfusion Injury in Kidney

Activation of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome cascade has a role in the pathogenesis of ischemia/reperfusion (IR) injury. There is growing evidence indicating cytochrome p450 (CYP450)-derived metabolites of n-3 and n-6 polyunsaturated fatty acids (PUFAs) possess both adverse and protective effects in the heart. CYP-derived epoxy metabolites are rapidly hydrolyzed by the soluble epoxide hydrolase (sEH). The current study hypothesized that the cardioprotective effects of inhibiting sEH involves limiting activation of the NLRP3 inflammasome. Isolated hearts from young wild-type (WT) and sEH null mice were perfused in the Langendorff mode with either vehicle or the specific sEH inhibitor t-AUCB. Improved post-ischemic functional recovery and better mitochondrial respiration were observed in both sEH null hearts or WT hearts perfused with t-AUCB. Inhibition of sEH markedly attenuated the activation of the NLRP3 inflammasome complex and limited the mitochondrial localization of the fission protein dynamin-related protein-1 (Drp-1) triggered by IR injury. Cardioprotective effects stemming from the inhibition of sEH included preserved activities of both cytosolic thioredoxin (Trx)-1 and mitochondrial Trx-2 antioxidant enzymes. Together, these data demonstrate that inhibiting sEH imparts cardioprotection against IR injury via maintaining post-ischemic mitochondrial function and attenuating a detrimental innate inflammatory response.

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Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00428.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. H2128-H2134 ◽

Cited By ~ 73

Author(s):

Atsuko Motoki ◽

Matthias J. Merkel ◽

William H. Packwood ◽

Zhiping Cao ◽

Lijuan Liu ◽

...

Keyword(s):

Myocardial Ischemia ◽

Reperfusion Injury ◽

Epoxide Hydrolase ◽

Gene Deletion ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Wild Type ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. EETs are formed from arachidonic acid during myocardial ischemia and play a protective role against ischemic cell death. Deletion of sEH has been shown to be protective against myocardial ischemia in the isolated heart preparation. We tested the hypothesis that sEH inactivation by targeted gene deletion or pharmacological inhibition reduces infarct size (I) after regional myocardial ischemia-reperfusion injury in vivo. Male C57BL\6J wild-type or sEH knockout mice were subjected to 40 min of left coronary artery (LCA) occlusion and 2 h of reperfusion. Wild-type mice were injected intraperitoneally with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), a sEH inhibitor, 30 min before LCA occlusion or during ischemia 10 min before reperfusion. 14,15-EET, the main substrate for sEH, was administered intravenously 15 min before LCA occlusion or during ischemia 5 min before reperfusion. The EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE) was given intravenously 15 min before reperfusion. Area at risk (AAR) and I were assessed using fluorescent microspheres and triphenyltetrazolium chloride, and I was expressed as I/AAR. I was significantly reduced in animals treated with AUDA-BE or 14,15-EET, independent of the time of administration. The cardioprotective effect of AUDA-BE was abolished by the EET antagonist 14,15-EEZE. Immunohistochemistry revealed abundant sEH protein expression in left ventricular tissue. Strategies to increase 14,15-EET, including sEH inactivation, may represent a novel therapeutic approach for cardioprotection against myocardial ischemia-reperfusion injury.

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Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPARγ

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00237.2016 ◽

2016 ◽

Vol 311 (4) ◽

pp. R676-R688 ◽

Cited By ~ 7

Author(s):

Ahmad Hanif ◽

Matthew L. Edin ◽

Darryl C. Zeldin ◽

Christophe Morisseau ◽

Mohammed A. Nayeem

Keyword(s):

Epoxide Hydrolase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Reactive Hyperemia ◽

Soluble Epoxide Hydrolase ◽

Mouse Heart ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Pparγ Agonist

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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Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-082 ◽

2012 ◽

Vol 90 (6) ◽

pp. 811-823 ◽

Cited By ~ 34

Author(s):

Sri N. Batchu ◽

Stephen B. Lee ◽

Victor Samokhvalov ◽

Ketul R. Chaudhary ◽

Haitham El-Sikhry ◽

...

Keyword(s):

Mitochondrial Function ◽

Epoxide Hydrolase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Soluble Epoxide Hydrolase ◽

Left Ventricular ◽

Ros Generation ◽

The Novel ◽

Active Metabolites ◽

Developed Pressure

Epoxyeicosatrienoic acids (EETs) are active metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase enzyme (sEH) to dihydroxyeicosatrienoic acid. EETs are known to render cardioprotection against ischemia reperfusion (IR) injury by maintaining mitochondrial function. We investigated the effect of a novel sEH inhibitor (sEHi) in limiting IR injury. Mouse hearts were perfused in Langendorff mode for 40 min and subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with 0.0, 0.1, 1.0 and 10.0 µmol·L–1 of the sEHi N-(2-chloro-4-methanesulfonyl-benzyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (BI00611953). Inhibition of sEH by BI00611953 significantly improved postischemic left-ventricular-developed pressure and reduced infarct size following IR compared with control hearts, and similar to hearts perfused with 11,12-EETs (1 µmol·L–1) and sEH–/– mice. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 µmol·L–1), or the plasma membrane KATP channels (pmKATP) inhibitor (glibenclamide, 10 µmol·L–1) abolished the improved recovery by BI00611953 (1 µmol·L–1). Mechanistic studies in H9c2 cells demonstrated that BI0611953 decreased ROS generation, caspase-3 activity, proteasome activity, increased HIF-1∝ DNA binding, and delayed the loss of mitochondrial membrane potential (ΔΨm) caused by anoxia–reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury.

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