Epoxyeicosatrienoic acids limit damage to mitochondrial function following stress in cardiac cells

D. Katragadda, S. N. Batchu, W. J. Cho, K. R. Chaudhary, J R Falck, J. M. Seubert

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58 Scopus citations

Abstract

Epoxyeicosatrienoic acids (EETs) are polyunsaturated fatty acids synthesized from arachidonic acid by CYP2J2 epoxygenase and inactivated by soluble epoxide hydrolase (sEH or Ephx2) to dihydroxyeicosatrienoic acids. Mitochondrial function following ischemic insult is a critical determinant of reperfusion-induced cell death in the myocardium. The objectives of the current study were to investigate the protective role of EETs in mitochondrial function. Mice with the targeted disruption of the Ephx2 gene, cardiomyocyte-specific overexpression of CYP2J2 or perfused with EETs all have improved postischemic LVDP recovery compared to wild-type (WT). Perfusion with the mPTP opener, atractyloside, abolished the improved postischemic functional recovery observed in CYP2J2 Tr, sEH null and EET perfused hearts. Electron micrographs demonstrated WT hearts to have increased mitochondrial fragmentation and T-tubule swelling compared to CYP2J2 Tr hearts following 20 min global ischemia and 20 min reperfusion. Direct effects of EETs on mitochondria were assessed in isolated rat cardiomyocytes and H9c2 cells. Laser-induced loss of mitochondrial membrane potential (ΔΨm) and mPTP opening was significantly reduced in cells treated with 14, 15-EET (1 μM). The EET protective effect was blocked by the putative EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (1 μM, 14, 15-EEZE), paxilline (10 μM, BKCa inhibitor) and 5HD (100 μM, KATP inhibitor). Our studies show that EETs can limit mitochondrial dysfunction following cellular stress via a K+ channel-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)867-875
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume46
Issue number6
DOIs
StatePublished - Jun 1 2009

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Keywords

  • Arachidonic acid
  • Cytochrome P450
  • Eicosanoid
  • Ischemia-reperfusion
  • K channel
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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