Epoxyeicosatrienoic acid prevents postischemic electrocardiogram abnormalities in an isolated heart model

S. N. Batchu, E. Law, D. R. Brocks, J. R. Falck, J. M. Seubert

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Cytochrome P450 epoxygenases metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) which are in turn converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). The main objective of this study was to investigate the protective effects of EETs following ischemic injury using an ex vivo electrocardiogram (EKG) model. Hearts from C57Bl/6, transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 (Tr) and wildtype (WT) littermates were excised and perfused with constant pressure in a Langendorff apparatus. Electrodes were placed superficially at the right atrium and left ventricle to assess EKG waveforms. In ischemic reperfusion experiments hearts were subjected to 20 min of global no-flow ischemia followed by 20 min of reperfusion (R20). The EKG from C57Bl/6 hearts perfused with 1 μM 14,15-EET showed less QT prolongation (QTc) and ST elevation (STE) (QTc = 41 ± 3, STE = 2.3 ± 0.3; R20: QTc = 42 ± 2 ms, STE = 1.2 ± 0.2mv) than control hearts (QTc = 36 ± 2, STE = 2.3 ± 0.2; R20: QTc = 53 ± 3 ms; STE = 3.6 ± 0.4mv). Similar results of reduced QT prolongation and ST elevation were observed in EKG recording from CYP2J2 Tr mice (QTc = 35 ± 1, STE = 1.9 ± 0.1; R20: QTc = 38 ± 4 ms, STE = 1.3 ± 0.2mv) compared to WT hearts. The putative epoxygenase inhibitor MS-PPOH (50 μM) and EET antagonist 14,15-EEZE (10 μM) both abolished the cardioprotective response, implicating EETs in this process. In addition, separate exposure to the KATP channel blockers glibenclamide (1 μM) and HMR1098 (10 μM), or the PKA protein inhibitor H89 (50 nM) during reperfusion abolished the improved repolarization in both the models. Consistent with a role of PKA, CYP2J2 Tr mice had an enhanced activation of the PKAα regulatory II subunit in plasma membrane following IR injury. The present data demonstrate that EETs can enhance the recovery of ventricular repolarization following ischemia, potentially by facilitating activation of K+ channels and PKA-dependent signaling.

Original languageEnglish (US)
Pages (from-to)67-74
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume46
Issue number1
DOIs
StatePublished - Jan 2009

Fingerprint

Electrocardiography
Acids
Reperfusion
Heart Ventricles
Ischemia
Epoxide Hydrolases
KATP Channels
Glyburide
Wounds and Injuries
Heart Atria
Cardiac Myocytes
Arachidonic Acid
Cytochrome P-450 Enzyme System
Transgenic Mice
Electrodes
Cell Membrane
Pressure
arachidonate epoxygenase
Proteins

Keywords

  • Epoxyeicosatrienoic acid
  • Ischemia-reperfusion
  • K channels
  • QTc interval
  • ST elevation (STE)

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Epoxyeicosatrienoic acid prevents postischemic electrocardiogram abnormalities in an isolated heart model. / Batchu, S. N.; Law, E.; Brocks, D. R.; Falck, J. R.; Seubert, J. M.

In: Journal of Molecular and Cellular Cardiology, Vol. 46, No. 1, 01.2009, p. 67-74.

Research output: Contribution to journalArticle

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