Inhibition of soluble epoxide hydrolase preserves cardiomyocytes

Role of STAT3 signaling

Matthias J. Merke, Lijuan Liu, Zhiping Cao, William Packwood, Jennifer Young, Nabil Alkayed, Donna M. Van Winkle

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), primarily 14,15-EET. EETs are derived from arachidonic acid via P-450 epoxygenases and are cardioprotective. We tested the hypothesis that sEH deficiency and pharmacological inhibition elicit tolerance to ischemia via EETmediated STAT3 signaling in vitro and in vivo. In addition, the relevance of single nucleotide polymorphisms (SNPs) of EPHX2 (the gene encoding sEH) on tolerance to oxygen and glucose deprivation and reoxygenation and glucose repletion (OGD/RGR) was assessed in male C57BL\6J (WT) or sEH knockout (sEHKO) cardiomyocytes by using transactivator of transcription (TAT)-mediated transduction with sEH mutant proteins. Cell death and hydrolase activity was lower in Arg287Gln EPHX2 mutants vs. nontransduced controls. Excess 14,15-EET and SEH inhibition did not improve cell survival in Arg287Gln mutants. In WT cells, the putative EET receptor antagonist, 14,15-EEZE, abolished the effect of 14,15-EET and sEH inhibition. Cotreatment with 14,15-EET and SEH inhibition did not provide increased protection. In vitro, STAT3 inhibition blocked 14,15-EET cytoprotection, but not the effect of SEH inhibition. However, STAT3 small interfering RNA (siRNA) abolished cytoprotection by 14,15-EET and sEH inhibition, but cells pretreated with JAK2 siRNA remained protected. In vivo, STAT3 inhibition abolished 14,15-EETmediated infarct size reduction. In summary, the Arg287Gln mutation is associated with improved tolerance against ischemia in vitro, and inhibition of sEH preserves cardiomyocyte viability following OGD/ RGR via an EET-dependent mechanism. In vivo and in vitro, 14,15-EET-mediated protection is mediated in part by STAT3.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number2
DOIs
StatePublished - 2010

Fingerprint

Epoxide Hydrolases
Cardiac Myocytes
Cytoprotection
Small Interfering RNA
Ischemia
Glucose
Trans-Activators
Hydrolases
Mutant Proteins
14,15-epoxy-5,8,11-eicosatrienoic acid
Arachidonic Acid
Single Nucleotide Polymorphism
Cell Survival
Cell Death
Pharmacology
Oxygen
Mutation
Acids
In Vitro Techniques

Keywords

  • 14,15-EET
  • Eicosanoid
  • N-adamantanyl-N′-dodecanoic acid urea
  • Oxygen and glucose deprivation
  • Reoxygenation and glucose repletion

ASJC Scopus subject areas

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

Cite this

Inhibition of soluble epoxide hydrolase preserves cardiomyocytes : Role of STAT3 signaling. / Merke, Matthias J.; Liu, Lijuan; Cao, Zhiping; Packwood, William; Young, Jennifer; Alkayed, Nabil; Van Winkle, Donna M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 298, No. 2, 2010.

Research output: Contribution to journalArticle

Merke, Matthias J. ; Liu, Lijuan ; Cao, Zhiping ; Packwood, William ; Young, Jennifer ; Alkayed, Nabil ; Van Winkle, Donna M. / Inhibition of soluble epoxide hydrolase preserves cardiomyocytes : Role of STAT3 signaling. In: American Journal of Physiology - Heart and Circulatory Physiology. 2010 ; Vol. 298, No. 2.
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