| First Author | Edin ML | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 9 | Pages | 3281-3292 |
| PubMed ID | 29298899 | Mgi Jnum | J:262336 |
| Mgi Id | MGI:6157248 | Doi | 10.1074/jbc.RA117.000298 |
| Citation | Edin ML, et al. (2018) Epoxide hydrolase 1 (EPHX1) hydrolyzes epoxyeicosanoids and impairs cardiac recovery after ischemia. J Biol Chem 293(9):3281-3292 |
| abstractText | Stimuli such as inflammation or hypoxia induce cytochrome P450 epoxygenase-mediated production of arachidonic acid-derived epoxyeicosatrienoic acids (EETs). EETs have cardioprotective, vasodilatory, angiogenic, anti-inflammatory, and analgesic effects, which are diminished by EET hydrolysis yielding biologically less active dihydroxyeicosatrienoic acids (DHETs). Previous in vitro assays have suggested that epoxide hydrolase 2 (EPHX2) is responsible for nearly all EET hydrolysis. EPHX1, which exhibits slow EET hydrolysis in vitro, is thought to contribute only marginally to EET hydrolysis. Using Ephx1(-/-), Ephx2(-/-), and Ephx1(-/-)Ephx2(-/-) mice, we show here that EPHX1 significantly contributes to EET hydrolysis in vivo Disruption of Ephx1 and/or Ephx2 genes did not induce compensatory changes in expression of other Ephx genes or CYP2 family epoxygenases. Plasma levels of 8,9-, 11,12-, and 14,15-DHET were reduced by 38, 44, and 67% in Ephx2(-/-) mice compared with wildtype (WT) mice, respectively; however, plasma from Ephx1(-/-)Ephx2(-/-) mice exhibited significantly greater reduction (100, 99, and 96%) of those respective DHETs. Kinetic assays and FRET experiments indicated that EPHX1 is a slow EET scavenger, but hydrolyzes EETs in a coupled reaction with cytochrome P450 to limit basal EET levels. Moreover, we also found that EPHX1 activities are biologically relevant, as Ephx1(-/-)Ephx2(-/-) hearts had significantly better postischemic functional recovery (71%) than both WT (31%) and Ephx2(-/-) (51%) hearts. These findings indicate that Ephx1(-/-)Ephx2(-/-) mice are a valuable model for assessing EET-mediated effects, uncover a new paradigm for EET metabolism, and suggest that dual EPHX1 and EPHX2 inhibition may represent a therapeutic approach to manage human pathologies such as myocardial infarction. |
