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

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.