Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: Role of oxylipins and PPARγ

Ahmad Hanif, Matthew L. Edin, Darryl C. Zeldin, Christophe Morisseau, Mohammed A. Nayeem

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH+/+, sEH−/−mice showed enhanced CRH, including greater repayment volume (RV; 28% higher,P< 0.001) and repayment/debt ratio (32% higher,P< 0.001). Oxylipins from the heart perfusates were analyzed by LC-MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline (P< 0.001) and 5.6-fold higher post-ischemia (P< 0.001) in sEH−/−compared with sEH+/+mice. Likewise, the baseline 9,10and 12,13-EpOME/DiHOME ratios were 3.2-fold (P< 0.01) and 3.7-fold (P< 0.001) higher, respectively in sEH−/−compared with sEH+/+mice. 13-HODE was also significantly increased at baseline by 71% (P< 0.01) in sEH−/−vs. sEH+/+mice. Levels of 5-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids were not significantly different between the two strains (P> 0.05), but were decreased postischemia in both groups (P = 0.02, P = 0.04, P = 0.05, P= 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPARγ) was demonstrated using a PPARγ-antagonist (T0070907), which reduced repayment volume by 25% in sEH+/+(P< 0.001) and 33% in sEH−/−mice (P< 0.01), and a PPARγ-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH+/+(P = 0.04) and sEH−/−mice (P = 0.04). l-NAME attenuated CRH in both sEH−/−and sEH+/+. These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response.

Original languageEnglish (US)
Pages (from-to)R676-R688
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume311
Issue number4
DOIs
StatePublished - 2016

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Keywords

  • Coronary reactive hyperemia
  • Dihydroxyei-cosatrienoic acids
  • Epoxyeicosatrienoic acids
  • Isolated perfused heart
  • Oxylipins
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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