1. Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress
- Author
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Batchu, Sri N., Lee, Stephen B., Samokhvalov, Victor, Chaudhary, Ketul R., Sikhry, Haitham El-, Weldon, Steven M., and Seubert, John M.
- Subjects
Hydrolases -- Physiological aspects -- Health aspects ,Ischemia -- Physiological aspects -- Genetic aspects -- Development and progression ,Metabolites -- Physiological aspects -- Health aspects ,Mitochondria -- Physiological aspects -- Health aspects ,Enzymes -- Physiological aspects -- Health aspects ,Biological sciences - Abstract
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.sup.-1] of the sEHi N-(2chloro-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.sup.-1]) and sE[H.sup.-/-] mice. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 µmol*[L.sup.-1),] or the plasma membrane [K.sub.ATP] channels (pm[K.sub.ATP)] inhibitor (glibenclamide, 10 µmol*[L.sup.-1)] abolished the improved recovery by BI00611953 (1 µmol*[L.sup.-1]). Mechanistic studies in H9c2 cells demonstrated that BI0611953 decreased ROS generation, caspase-3 activity, proteasome activity, increased HIF-1[varies] DNA binding, and delayed the loss of mitochondrial membrane potential (Δ[Ψ.sub.m]) caused by anoxia-reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury. Key words: epoxyeicosatrienoic acid, soluble epoxide hydrolase, ischemia-reperfusion, pm[K.sub.ATP] channels and sEH inhibitors. Les acides epoxyeicosatrienoiques (EET) sont des metabolites actifs de l'acide arachidonique qui sont inactives par l'epoxyde hydrolase soluble (sEH) en acide dihydroxyeicosatrienoi'que. Les EET sont connus pour conferer une cardioprotection contre les dommages causes par l'ischemie reperfusion (IR) en maintenant la fonction mitochondriale. Nous avons examine l'effet d'un nouvel inhibiteur de la sEH (sEHi) sur le controle du dommage cause par l'IR. Des coeurs de souris ont ete perfuses dans le systeme de Langendorff pendant 40 min et soumis a une ischemie statique globale de 20 min, suivie d'une reperfusion de 40 min. Les coeurs ont ete perfuses avec le sEHi, le BI00611953 (N-(2-chloro-4-methanesulfonyl-benzyl)-6(2,2,2-trifluoro-ethoxy)-nicotinamide) (0, 0,1, 1,0, et 10,0 µmol*[L.sup.-1]). L'inhibition de la sEH par le BI00611953 ameliorait significativement la pression ventriculaire gauche post-ischemique et reduisait la taille de l'infarctus apres l'IR comparativement aux coeurs controles et similairement aux coeurs perfuses avec des 11,12-EET (1 µmol*[L.sup.-1]) et aux souris sE[H.sup.-/-]. La perfusion avec un antagoniste presume du recepteur des EET, l'acide 14,15-epoxyei'cosa-5(Z)-enoi'que (14,15-EEZE, 10 µmol*[L.sup.-1]), ou avec un inhibiteur des canaux KATP de la membrane plasmique (pm[K.sub.ATP)] (glibenclamide, 10 µmol*[L.sup.-1]) supprimait l'amelioration de la recuperation induite par le BI00611593. Des etudes mecanistiques realisees chez les cellules H9c2 ont demontre que le BI00611593 diminuait la generation d'ERO, la caspase-3 et l'activite du proteasome, augmentait la liaison du HIF-1 a l'ADN, et retardait la perte de potentiel membranaire mitochondrial (Δ[Ψ.sub.m]) causee par l'anoxie-reoxygenation. L'ensemble de ces donnees demontre que ce nouvel sEHi, le BI00611953, un compose a base de nicotinamide, confere une cardioprotection significative contre les dommages causes par l' ischemie reperfusion Mots-cles : acide epoxyei'cosatrienoi'que, epoxyde hydrolase soluble, ischemie-reperfusion, canaux pm[K.sub.ATP,] inhibiteurs de la sEH., Introduction Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP) epoxygenase metabolites of arachidonic acid (AA); potent intracellular lipid signaling molecules that exist as 4 regioisomeric metabolites: 5,6-, 8,9-, 11,12-, and 14,15-EETs [...]
- Published
- 2012
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