Epoxyeicosatrienoic acids in cardioprotection: Ischemic versus reperfusion injury

Kasem Nithipatikom, Jeannine M. Moore, Marilyn A. Isbell, J R Falck, Garrett J. Gross

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Cytochrome P-450 (CYP) epoxygenases and their arachidonic acid (AA) metabolites, the epoxyeicosatrienoic acids (EETs), have been shown to produce increases in postischemic function via ATP-sensitive potassium channels (K ATP); however, the direct effects of EETs on infarct size (IS) have not been investigated. We demonstrate that two major regioisomers of CYP epoxygenases, 11,12-EET and 14,15-EET, significantly reduced IS in dogs compared to control (22.1 ± 1.8%), whether administered 15 min before 60 min of coronary occlusion (6.4 ± 1.9%, 11,12-EET; and 8.4 ± 2.4%, 14.15-EET) or 5 min before 3 h of reperfusion (8.8 ± 2.1%, 11,12-EET; and 9.7 ± 1.4%, 14,15-EET). Pretreatment with the epoxide hydrolase metabolite of 14,15-EET, 14,15-dihydroxyeicosatrienoic acid, had no effect. The protective effect of 11,12-EET was abolished (24.3 ± 4.6%) by the K ATP channel antagonist glibenclamide. Furthermore, one 5-min period of ischemic preconditioning (IPC) reduced IS to a similar extent (8.7 ± 2.8%) to that observed with the EETs. The selective CYP epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), did not block the effect of IPC. However, administration of MS-PPOH concomitantly with N-methylsulfonyl-12, 12-dibromododec-11-enanide (DDMS), a selective inhibitor of endogenous CYP ω-hydroxylases, abolished the reduction in myocardial IS expressed as a percentage of area at risk (IS/AAR) produced by DDMS (4.6 ± 1.2%, DDMS; and 22.2 ± 3.4%, MS-PPOH ± DDMS). These data suggest that 11,12-EET and 14,15-EET produce reductions in IS/AAR primarily at reperfusion. Conversely, inhibition of CYP epoxygenases and endogenous EET formation by MS-PPOH, in the presence of the CYP ω-hydroxylase inhibitor DDMS blocked cardioprotection, which suggests that endogenous EETs are important for the beneficial effects observed when CYP ω-hydroxylases are inhibited. Finally, the protective effects of EETs are mediated by cardiac KATP channels.

Original languageEnglish (US)
Pages (from-to)H537-H542
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume291
Issue number2
DOIs
StatePublished - Aug 10 2006

Keywords

  • 11,12-epoxyeicosatrienoic acid
  • 14,15-epoxyeicosatrienoic acid
  • 20-hydroxyeicosatetraenoic acid
  • Adenosine 5′-triphosphate-sensitive potassium channels
  • Cytochrome P-450 epoxygenase
  • Ischemic preconditioning

ASJC Scopus subject areas

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

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