Soluble Epoxide Hydrolase Gene Deletion is Protective Against Myocardial Ischemia‐Reperfusion Injury In Vivo

Abstract

Epoxyeicosatrienoic acids (EETs) are metabolized by soluble epoxide hydrolase (sEH). Targeted disruption of the sEH gene enhances post‐ischemic contractile function in isolated hearts and exogenous administration of EETs limits myocardial infarct size in vivo. We tested the hypothesis that sEH gene deletion is cardioprotective.Male C57BL\6J wild‐type (WT) mice or sEH knockout (sEHKO) mice were subjected to 40 min coronary artery occlusion and 120 min reperfusion. Area‐at‐risk (AAR) and infarct size (I) were assessed using fluorescent microspheres and triphenyl tetrazolium chloride. Infarct size is expressed as I/AAR (mean ± SEM). Myocardial sEH protein content was assessed by immunoblot and its distribution by immunohistochemistry (IHC).I/AAR was reduced by 25±9% in sEHKO compared to WT (37±3% n=10 vs. 49 ± 3% n=8, p<0.05). AAR/heart volume was comparable between groups (27 ± 4% vs. 29 ± 4%). Western blot confirmed the absence of sEH in sEHKO and its presence in WT hearts. IHC was positive for sEH in cardiomyocytes in WT but not sEHKO mice.Cardioprotection from targeted deletion of sEH is likely due to increased endogenous myocardial EET levels. Infusion of EETs or inhibition of sEH may serve as a novel therapeutic option for cardioprotection during coronary revascularization and cardiac transplantation. Support: VA Merit Review 317 (DMVW) and RO1 NS44313 (NJA).