Chaudhary KR, Abukhashim M, Hwang SH, Hammock BD, Seubert JM
Inhibition of soluble epoxide hydrolase by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) is protective against ischemia reperfusion injury. [JOURNAL ARTICLE]
J Cardiovasc Pharmacol 2009 Oct 9.
Arachidonic acid, a polyunsaturated fatty acid, can be metabolized to cardioprotective epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenases, which are subsequently hydrolyzed to less bioactive dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). To study the effects of pharmacological inhibitor of sEH (sEHi), C57BL6 mice hearts were perfused in Langendorff mode for 40min of baseline and subjected to 30min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with the sEHi, trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 0.05 muM, 0.1 muM, 0.5 muM and 1 muM). To study the mechanism(s), hearts were perfused with 0.1 muM t-AUCB in the presence or absence of putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 muM) or phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin (200 nM) or LY294002 (5 muM). Infarct size was determined at the end of 2 h reperfusion by TTC staining. Inhibition of sEH by t-AUCB significantly improved postischemic left ventricular developed pressure (LVDP) recovery and reduced the infarct size following ischemia-reperfusion, as compared to control hearts. Perfusion with 14,15-EEZE, wortmannin or LY294002 prior to ischemia abolished the cardioprotective phenotype; however, co-perfusion of both t-AUCB and 11,12-EET did not result in an additive effect on improved LVDP recovery. Together, our data suggest that pharmacological inhibition of sEH by t-AUCB is cardioprotective.
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