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 postischemia (P < 0.001) in sEH(-/-) compared with sEH(-/-) mice. Likewise, the baseline 9,10-and 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 (PPAR gamma) was demonstrated using a PPAR gamma -antagonist (T0070907), which reduced repayment volume by 25% in sEH(+/+) (P < 0.001) and 33% in sEH(-/-) mice (P < 0.01), and a PPAR gamma-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.