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, J R Falck, Holly Roberts, Howard A. Rockman, Elizabeth Murphy, Darryl C. Zeldin

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144 Scopus citations

Abstract

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 (KATP) inhibitor glibenclamide (1 μmol/L), the mitochondrial KATP (mitoKATP) inhibitor 5-hydroxydecanoate (100 to 200 μmol/L), or the Ca-sensitive K channel (KCa) 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-3β (GSK-3β) 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.

Original languageEnglish (US)
Pages (from-to)442-450
Number of pages9
JournalCirculation research
Volume99
Issue number4
DOIs
StatePublished - Aug 1 2006

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Keywords

  • Arachidonic acid
  • Cytochrome P450
  • Eicosanoid
  • Ischemia/reperfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Seubert, J. M., Sinal, C. J., Graves, J., Degraff, L. M., Bradbury, J. A., Lee, C. R., Goralski, K., Carey, M. A., Luria, A., Newman, J. W., Hammock, B. D., Falck, J. R., Roberts, H., Rockman, H. A., Murphy, E., & Zeldin, D. C. (2006). Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circulation research, 99(4), 442-450. https://doi.org/10.1161/01.RES.0000237390.92932.37