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Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function.

Publication ,  Journal Article
Seubert, JM; Sinal, CJ; Graves, J; DeGraff, LM; Bradbury, JA; Lee, CR; Goralski, K; Carey, MA; Luria, A; Newman, JW; Hammock, BD; Falck, JR ...
Published in: Circ Res
August 18, 2006

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 micromol/L), the ATP-sensitive K+ channel (K(ATP)) inhibitor glibenclamide (1 micromol/L), the mitochondrial K(ATP) (mitoK(ATP)) inhibitor 5-hydroxydecanoate (100 to 200 micromol/L), or the Ca2+-sensitive K+ channel (K(Ca)) inhibitor paxilline (10 micromol/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-3beta (GSK-3beta) 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.

Duke Scholars

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

August 18, 2006

Volume

99

Issue

4

Start / End Page

442 / 450

Location

United States

Related Subject Headings

  • Myocardium
  • Myocardial Ischemia
  • Myocardial Contraction
  • Mitochondria, Heart
  • Mice, Inbred C57BL
  • Mice
  • Heart
  • Glyburide
  • Epoxide Hydrolases
  • Echocardiography, Transesophageal
 

Citation

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Seubert, J. M., Sinal, C. J., Graves, J., DeGraff, L. M., Bradbury, J. A., Lee, C. R., … Zeldin, D. C. (2006). Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circ Res, 99(4), 442–450. https://doi.org/10.1161/01.RES.0000237390.92932.37
Seubert, John M., Christopher J. Sinal, Joan Graves, Laura M. DeGraff, J Alyce Bradbury, Craig R. Lee, Kerry Goralski, et al. “Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function.Circ Res 99, no. 4 (August 18, 2006): 442–50. https://doi.org/10.1161/01.RES.0000237390.92932.37.
Seubert JM, Sinal CJ, Graves J, DeGraff LM, Bradbury JA, Lee CR, et al. Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circ Res. 2006 Aug 18;99(4):442–50.
Seubert, John M., et al. “Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function.Circ Res, vol. 99, no. 4, Aug. 2006, pp. 442–50. Pubmed, doi:10.1161/01.RES.0000237390.92932.37.
Seubert JM, Sinal CJ, Graves J, DeGraff LM, Bradbury JA, Lee CR, Goralski K, Carey MA, Luria A, Newman JW, Hammock BD, Falck JR, Roberts H, Rockman HA, Murphy E, Zeldin DC. Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circ Res. 2006 Aug 18;99(4):442–450.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

August 18, 2006

Volume

99

Issue

4

Start / End Page

442 / 450

Location

United States

Related Subject Headings

  • Myocardium
  • Myocardial Ischemia
  • Myocardial Contraction
  • Mitochondria, Heart
  • Mice, Inbred C57BL
  • Mice
  • Heart
  • Glyburide
  • Epoxide Hydrolases
  • Echocardiography, Transesophageal