Epoxide Hydrolase 1 Regulates Epoxyeicosanoid Hydrolysis and Postischemic Cardiac Recovery

Authors

• ML Eden
• BG Hamedani
• A Gruzdev
• FB Lih
• SJ Arbes III
• R Singh
• AC Orjuela Leon
• JP Graves
• JA Bradbury
• LM DeGraff
• SL Hoopes
• M Arand
• DC Zeldin

Abstract

Stimuli such as inflammation or hypoxia induce production of epoxyeicosatrienoic acids (EETs) from arachidonic acid by cytochrome P450 epoxygenases. EETs have cardioprotective, vasodilatory, pro-angiogenic, anti-inflammatory and analgesic effects, which are diminished by hydrolysis to biologically less active dihydroxyeicosatrienoic acids (DHETs). Prior in vitro assays suggest that epoxide hydrolase 2 (EPHX2) is responsible for nearly all EET hydrolysis; epoxide hydrolase 1 (EPHX1), which exhibits slow hydrolysis of EETs in vitro, is thought to contribute marginally. Using Ephx1-/-, Ephx2-/- and Ephx1-/- Ephx2-/- mice, we demonstrate that EPHX1 significantly contributes to EET hydrolysis in vivo. Indeed, plasma levels of 8,9-, 11,12-, and 14,15-DHET were reduced by 38%, 44%, and 67% in Ephx2-/- mice compared to wild-type (WT) mice; however, plasma from Ephx1-/- Ephx2-/- mice exhibited significantly greater reduction (100%, 99%, and 96%) of those respective DHETs. Kinetic assays and FRET experiments indicate that EPHX1 is a slow EET scavenger, but regulates steady-state EET levels in a coupled reaction with cytochrome P450s. Moreover, EPHX1 actions are biologically relevant, as Ephx1-/- Ephx2-/- hearts have significantly improved post-ischemic functional recovery (71%) compared to both WT (31%) and Ephx2-/- (51%) hearts (p

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