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

74 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume291
Issue number2
DOIs
StatePublished - 2006

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Reperfusion Injury
Cytochrome P-450 Enzyme System
Mixed Function Oxygenases
Acids
KATP Channels
Ischemic Preconditioning
Reperfusion
Adenosine Triphosphate
Epoxide Hydrolases
Glyburide
Coronary Occlusion
Arachidonic Acid
Myocardial Infarction
DDMS
11,12-epoxy-5,8,14-eicosatrienoic acid
Dogs
14,15-epoxy-5,8,11-eicosatrienoic acid
caproamide
Cytochrome P-450 Enzyme Inhibitors

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

Cite this

Epoxyeicosatrienoic acids in cardioprotection : Ischemic versus reperfusion injury. / Nithipatikom, Kasem; Moore, Jeannine M.; Isbell, Marilyn A.; Falck, J R; Gross, Garrett J.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 291, No. 2, 2006.

Research output: Contribution to journalArticle

Nithipatikom, Kasem ; Moore, Jeannine M. ; Isbell, Marilyn A. ; Falck, J R ; Gross, Garrett J. / Epoxyeicosatrienoic acids in cardioprotection : Ischemic versus reperfusion injury. In: American Journal of Physiology - Heart and Circulatory Physiology. 2006 ; Vol. 291, No. 2.
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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.",
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T2 - Ischemic versus reperfusion injury

AU - Nithipatikom, Kasem

AU - Moore, Jeannine M.

AU - Isbell, Marilyn A.

AU - Falck, J R

AU - Gross, Garrett J.

PY - 2006

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N2 - 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.

AB - 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.

KW - 11,12-epoxyeicosatrienoic acid

KW - 14,15-epoxyeicosatrienoic acid

KW - 20-hydroxyeicosatetraenoic acid

KW - Adenosine 5′-triphosphate-sensitive potassium channels

KW - Cytochrome P-450 epoxygenase

KW - Ischemic preconditioning

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