Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo

Atsuko Motoki, Matthias Merkel, William H. Packwood, Zhiping Cao, Lijuan Liu, Jeffrey Iliff, Nabil Alkayed, Donna M. Van Winkle

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. EETs are formed from arachidonic acid during myocardial ischemia and play a protective role against ischemic cell death. Deletion of sEH has been shown to be protective against myocardial ischemia in the isolated heart preparation. We tested the hypothesis that sEH inactivation by targeted gene deletion or pharmacological inhibition reduces infarct size (I) after regional myocardial ischemia-reperfusion injury in vivo. Male C57BL\6J wild-type or sEH knockout mice were subjected to 40 min of left coronary artery (LCA) occlusion and 2 h of reperfusion. Wild-type mice were injected intraperitoneally with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), a sEH inhibitor, 30 min before LCA occlusion or during ischemia 10 min before reperfusion. 14,15-EET, the main substrate for sEH, was administered intravenously 15 min before LCA occlusion or during ischemia 5 min before reperfusion. The EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE) was given intravenously 15 min before reperfusion. Area at risk (AAR) and I were assessed using fluorescent microspheres and triphenyltetrazolium chloride, and I was expressed as I/AAR. I was significantly reduced in animals treated with AUDA-BE or 14,15-EET, independent of the time of administration. The cardioprotective effect of AUDA-BE was abolished by the EET antagonist 14,15-EEZE. Immunohistochemistry revealed abundant sEH protein expression in left ventricular tissue. Strategies to increase 14,15-EET, including sEH inactivation, may represent a novel therapeutic approach for cardioprotection against myocardial ischemia-reperfusion injury.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 2008

Fingerprint

Myocardial Reperfusion Injury
Epoxide Hydrolases
Gene Deletion
Reperfusion Injury
Myocardial Ischemia
Reperfusion
Coronary Occlusion
Coronary Vessels
Esters
Ischemia
Acids
Microspheres
Arachidonic Acid
Knockout Mice
Cell Death
Immunohistochemistry
Pharmacology

Keywords

  • 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester
  • 14,15-epoxyeicosatrienoic acids

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo. / Motoki, Atsuko; Merkel, Matthias; Packwood, William H.; Cao, Zhiping; Liu, Lijuan; Iliff, Jeffrey; Alkayed, Nabil; Van Winkle, Donna M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 295, No. 5, 11.2008.

Research output: Contribution to journalArticle

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AU - Iliff, Jeffrey

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AU - Van Winkle, Donna M.

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