Deletion of Soluble Epoxide Hydrolase Modulates Coronary Reactive Hyperemia in Isolated Mouse Heart

Abstract

Coronary reactive hyperemia (RH) is impaired in hypertrophic hearts. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia / reperfusion injury. Soluble epoxide hydrolase (sEH) is the main enzyme responsible for EETs breakdown. EETs level is increased in sEH knock‐out mice (sEH‐/‐). We hypothesized that in the absence of sEH, isolated mouse heart exhibits increased RH through increased generation of EETs in response to no‐flow ischemia compared to wild type (sEH+/+). Coronary flow (CF) in isolated sEH+/+ and sEH‐/‐ mouse heart was measured using Langendorff system. Perfused isolated heart was exposed to 15 second ischemia and RH was assessed. Following ischemia, flow repayment volume (RV) was significantly higher in sEH‐/‐ compared to sEH+/+ (7.6 ± 0.5 in sEH‐/‐ vs. 5.9 ± 0.7 in sEH+/+, p<0.05). Moreover, sEH‐/‐ exhibited significantly higher repayment to debt ratio when compared to sEH+/+ hearts (2.1 ± 0.2 in sEH‐/‐ vs. 1.5 ± 0.1 in sEH+/+, p<0.05). Upstream of EETs; the increased in RV in sEH‐/‐ was significantly decreased by SCH‐58261 (a selective adenosine A2A antagonist, 1.0 mM) (6.8 ± 0.8 in sEH‐/‐ without SCH‐58261 vs. 3.5 ± 0.3 with SCH‐58261, p<0.05). Also, downstream of EETs; T‐0070907 (a selective PPARg antagonist, 10.0 mM) significantly decreased RV in sEH‐/‐ (7.7 ± 1.2 in sEH‐/‐ without T‐0070907 vs. 5.4 ± 0.8 with T‐0070907, p<0.05).Our results demonstrate that deletion of sEH increases RH compared to WT and that the enhanced RH is significantly decreased by SCH‐58261 and T‐0070907. These data suggest that targeting or silencing sEH may have a beneficial effect on myocardial recovery from ischemia. Supported by HL‐114559 to MAN and z01‐ES025034 to DCZ