Epoxyeicosatrienoic acids and cardioprotection: The road to translation

Oni‐Orisan, Akinyemi; Alsaleh, Nasser B.; Lee, Craig; Seubert, John M.

doi:10.1016/j.yjmcc.2014.05.016

Cited by 60 publications

(68 citation statements)

References 115 publications

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“…Transgenic mouse models have been created that overexpress human CYPs in specific tissues. Genetic and biomarker-based studies are being used to associate disease risk with CYP variants or alterations in CYP activity in human subjects (Oni-Orisan et al, 2014), and there is growing understanding of the factors that account for variability in CYP expression and activity among individuals (Shahabi, Siest, Meyer, et al, 2014). Future progress will benefit from the continued application of these strategies and other emerging technologies.…”

Section: Resultsmentioning

confidence: 99%

“…EETs produce their effects by activating a variety of signaling pathways and ion channels. The functions of EETs in cardiovascular disease, and their signaling mechanisms, are described in detail in a number of recent reviews (Deng et al, 2010;Fan, Muroya, & Roman, 2015;Fleming, 2014;Imig, 2012;Imig, Simpkins, Renic, & Harder, 2011;Oni-Orisan et al, 2014;Zhang, Kodani, & Hammock, 2014). CYP epoxygenases are expressed in endothelium, kidney tubules, cardiomyocytes, certain neurons, and glia.…”

Section: Chronic Inflammation and Cardiovascular Diseasementioning

confidence: 99%

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Role of Cytochrome P450s in Inflammation

Christmas

2015

Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer

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Section: Resultsmentioning

confidence: 99%

Section: Chronic Inflammation and Cardiovascular Diseasementioning

confidence: 99%

Role of Cytochrome P450s in Inflammation

Christmas

2015

Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer

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“…Preclinical studies have demonstrated that EPHX2 disruption or inhibition improves postischemic cardiac functional recovery and reduces MI (4,[36][37][38]. EPHX2 inhibitors, which have completed phase I clinical trials (39), have been proposed as treatments for patients suffering MI (40,41).…”

Section: Ephx1 Regulates Eet Hydrolysis and Postischemic Recoverymentioning

confidence: 99%

Epoxide hydrolase 1 (EPHX1) hydrolyzes epoxyeicosanoids and impairs cardiac recovery after ischemia

Edin

Hamedani

Gruzdev

et al. 2018

Journal of Biological Chemistry

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Stimuli such as inflammation or hypoxia induce cytochrome P450 epoxygenase-mediated production of arachidonic acid-derived epoxyeicosatrienoic acids (EETs). EETs have cardioprotective, vasodilatory, angiogenic, antiinflammatory, 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 herein 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 wild-type (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 cytochromes 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. ________________________________________ Cytochrome P450 epoxygenases can oxidize arachidonic acid (AA) to form epoxyeicosatrienoic acids (EETs) which have potent cardiovascular effects. The biological effects of EETs are shortlived in that they are rapidly hydrolyzed to less active dihydroxyeicosatrienoic acids (DHETs) by EPHX2, also known as soluble epoxide hydrolase (sEH) (1). Indeed, Ephx2 -/-mice have increased EETs, decreased DHETs and improved outcomes in vascular disease models, which provide the basis for development of pharmacological EPHX2 inhibitors (1,2). EPHX2 inhibition increases EET levels in vivo, and leads to cardioprotective, vasodilatory, angiogenic, anti-inflammatory and analgesic effects (1-3). EPHX1 Regulates EET Hydrolysis and Postischemic Recovery2 EPHX2 inhibitors, which have completed phase I clinical trials, are under investigation for treatment of neuropathic pain, and may hold promise for treatment of other ailments. However, genetic disruption of Ephx2 or EPHX2 pharmacological inhibition does not completely abolish EET hydrolysis in vivo. Among the EETs, EPHX2 has the biggest effect on levels of its preferred substrate, 14,15-EET, but has diminishing effects on 11,12-and 8,9-...

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“…Promoting the effects of EETs yields potent cardiovascular protective effects in preclinical models of vascular infl ammation, atherosclerosis, and myocardial ischemiareperfusion injury (5)(6)(7). In epidemiological studies, associations between functional polymorphisms in genes responsible for EET biosynthesis ( CYP2C8, CYP2J2 ) or EET hydrolysis ( EPHX2 ) and the development of CAD have been reported (8)(9)(10).…”

Section: Gene Expression In Peripheral Blood Mononuclear Cellsmentioning

confidence: 99%