title: Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPARγ.
abstract: The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH+/+, sEH-/-mice showed enhanced CRH, including greater repayment volume (RV; 28% higher, P < 0.001) and repayment/debt ratio (32% higher, P < 0.001). Oxylipins from the heart perfusates were analyzed by LC-MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline (P < 0.001) and 5.6-fold higher post-ischemia (P < 0.001) in sEH-/-compared with sEH+/+mice. Likewise, the baseline 9,10- and 12,13-EpOME/DiHOME ratios were 3.2-fold (P < 0.01) and 3.7-fold (P < 0.001) higher, respectively in sEH-/-compared with sEH+/+mice. 13-HODE was also significantly increased at baseline by 71% (P < 0.01) in sEH-/-vs. sEH+/+mice. Levels of 5-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids were not significantly different between the two strains (P > 0.05), but were decreased postischemia in both groups (P = 0.02, P = 0.04, P = 0.05, P = 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPARγ) was demonstrated using a PPARγ-antagonist (T0070907), which reduced repayment volume by 25% in sEH+/+(P < 0.001) and 33% in sEH-/-mice (P < 0.01), and a PPARγ-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH+/+(P = 0.04) and sEH-/-mice (P = 0.04). l-NAME attenuated CRH in both sEH-/-and sEH+/+These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response.
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Hanif
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina; and.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina; and.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: University of California at Davis, Davis, California.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia; mnayeem@hsc.wvu.edu.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Nayeem
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000503:physiopathology*; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006940:Hyperemia / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice / Q000378:metabolism*; D018345:Mice, Knockout; D054883:Oxylipins / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*
chemical_list: D054883:Oxylipins; D047495:PPAR gamma; D004851:Epoxide Hydrolases
keywords: coronary reactive hyperemia; dihydroxyeicosatrienoic acids; epoxyeicosatrienoic acids; isolated perfused heart; oxylipins; soluble epoxide hydrolase