Original Research ArticleReduced coronary reactive hyperemia in mice was reversed by the soluble epoxide hydrolase inhibitor (t-AUCB): Role of adenosine A2A receptor and plasma oxylipins

•Adenosine A2AAR is involved in the cardiprotective coronary reactive hyperemia (CRH) in response to ischemia.•Soluble epoxide hydrolase (sEH) breaks down epoxyeicosatrienoic acids (EETs), which are cardioprotective metabolites.•A2AAR deletion is associated with changed oxylipin profiles consistent between plasma and heart perfusate samples.•Oxylipin changes in A2AAR−/− mice indicate an increased proinflammatory state.•Inhibition of either sEH or ω-hydroxylases reversed the reduced CRH in A2AAR−/− mice.

Coronary reactive hyperemia (CRH) protects the heart against ischemia. Adenosine A2AAR-deficient (A2AAR−/−) mice have increased expression of soluble epoxide hydrolase (sEH); the enzyme responsible for breaking down the cardioprotective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). sEH-inhibition enhances CRH, increases EETs, and modulates oxylipin profiles. We investigated the changes of oxylipins and their impact on CRH in A2AAR−/− and wild type (WT) mice. We hypothesized that the attenuated CRH in A2AAR−/− mice is mediated by changes in oxylipin profiles, and that it can be reversed by either sEH- or ω-hydroxylases-inhibition. Compared to WT mice, A2AAR−/− mice had attenuated CRH and changed oxylipin profiles, which were consistent between plasma and heart perfusate samples, including decreased EET/DHET ratios, and increased hydroxyeicosatetraenoic acids (HETEs). Plasma oxylipns in A2AAR−/− mice indicated an increased proinflammatory state including increased ω-terminal HETEs, decreased epoxyoctadecaenoic/dihydroxyoctadecaenoic acids (EpOMEs/DiHOMEs) ratios, increased 9-hydroxyoctadecadienoic acid, and increased prostanoids. Inhibition of either sEH or ω-hydroxylases reversed the reduced CRH in A2AAR−/− mice. In WT and sEH−/− mice, blocking A2AAR decreased CRH. These data demonstrate that A2AAR-deletion was associated with changes in oxylipin profiles, which may contribute to the attenuated CRH. Also, inhibition of sEH and ω-hydroxylases reversed the reduction in CRH.