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(Circulation Research. 2006;99:442.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Role of Soluble Epoxide Hydrolase in Postischemic Recovery of Heart Contractile Function

John M. Seubert^*, Christopher J. Sinal^*, Joan Graves, Laura M. DeGraff, J. Alyce Bradbury, Craig R. Lee, Kerry Goralski, Michelle A. Carey, Ayala Luria, John W. Newman, Bruce D. Hammock, John R. Falck, Holly Roberts, Howard A. Rockman, Elizabeth Murphy, Darryl C. Zeldin

From the Faculty of Pharmacy and Pharmaceutical Sciences (J.M.S.), University of Alberta, Edmonton, AB, Canada; the Division of Intramural Research (J.M.S., J.G., L.M.D., J.A.B., C.R.L., M.A.C., E.M., D.C.Z.), NIEHS/NIH, Research Triangle Park, NC; the Department of Pharmacology (C.J.S., K.G.), Dalhousie University, Halifax, NS, Canada; the Department of Entomology and Cancer Research Center (A.L., J.W.N., B.D.H.), University of California, Davis, Calif; the Departments of Biochemistry and Pharmacology (J.R.F.), University of Texas Southwestern Medical Center, Dallas, Tex; the Department of Medicine (H.R., H.A.R., D.C.Z.), Duke University Medical Center, Durham, NC; and the School of Pharmacy (C.R.L.), University of North Carolina at Chapel Hill, Chapel Hill, NC.

Correspondence to Darryl C. Zeldin, MD, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709. E-mail zeldin{at}niehs.nih.gov

Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which are converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (Ephx2, sEH). To examine the functional role of sEH in the heart, mice with targeted disruption of the Ephx2 gene were studied. Hearts from sEH null mice have undetectable levels of sEH mRNA and protein and cannot convert EETs to DHETs. sEH null mice have normal heart anatomy and basal contractile function, but have higher fatty acid epoxide:diol ratios in plasma and cardiomyocyte cell culture media compared with wild type (WT). sEH null hearts have improved recovery of left ventricular developed pressure (LVDP) and less infarction compared with WT hearts after 20 minutes ischemia. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (10 to 100 nmol/L) before ischemia abolishes this cardioprotective phenotype. Inhibitor studies demonstrate that perfusion with phosphatidylinositol-3 kinase (PI3K) inhibitors wortmannin (200 nmol/L) or LY294002 (5 µmol/L), the ATP-sensitive K⁺ channel (K_ATP) inhibitor glibenclamide (1 µmol/L), the mitochondrial K_ATP (mitoK_ATP) inhibitor 5-hydroxydecanoate (100 to 200 µmol/L), or the Ca²⁺-sensitive K⁺ channel (K_Ca) inhibitor paxilline (10 µmol/L) abolishes the cardioprotection in sEH null hearts. Consistent with increased activation of the PI3K cascade, sEH null mice exhibit increased cardiac expression of glycogen synthase kinase-3ß (GSK-3ß) phospho-protein after ischemia. Together, these data suggest that targeted disruption of sEH increases the availability of cardioprotective EETs that work by activating PI3K signaling pathways and K⁺ channels.

Key Words: arachidonic acid • cytochrome P450 • eicosanoid • ischemia/reperfusion

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