Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress

Sri N. Batchu, Stephen B. Lee, Victor Samokhvalov, Ketul R. Chaudhary, Haitham El-Sikhry, Steven M. Weldon, John M. Seubert

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

41 Citas (Scopus)

Resumen

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 (Δφm) caused by anoxia-reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury.

Idioma originalEnglish
Páginas (desde-hasta)811-823
Número de páginas13
PublicaciónCanadian Journal of Physiology and Pharmacology
Volumen90
N.º6
DOI
EstadoPublished - 2012
Publicado de forma externa

ASJC Scopus Subject Areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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