title: Differential effects of soluble epoxide hydrolase inhibition and CYP2J2 overexpression on postischemic cardiac function in aged mice.
abstract: Cardioprotective effects of epoxyeicosatrienoic acids (EETs) have been demonstrated in models of young mice with either the cardiomyocyte specific over-expression of cytochrome P450 2J2 (CYP2J2 Tr) or deletion of soluble epoxide hydrolase (sEH null). In this study we examined differences in EET-induced cardioprotection in young (2 months) and aged (12 months) CYP2J2 Tr and sEHnull mice using Langendorff isolated perfused heart model. Improved postischemic functional recovery was observed in both young and aged sEH null mice compared to age matched WT. Conversely, the cardioprotective effect observed in young CYP2J2 Tr was lost in aged CYP2J2 Tr mice. The loss of cardioprotection in aged CYP2J2 Tr was regained following perfusion with the sEH inhibitor t-AUCB. Data demonstrated increased levels of leukotoxin diol (DiHOME) and oxidative stress as well decreased protein phosphatase 2A (PP2A) activation in aged CYP2J2 Tr. In conclusion, inhibition of sEH and EET-induced cardioprotection is maintained in aged mice. However, the loss of protective effects observed in aged CYP2J2 Tr might be attributed to increased levels of DiHOME, oxidative stress and/or decreased PP2A activity.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Ketul R
authors.initials: KR
authors.lastname: Chaudhary
authors.forename: Beshay N M
authors.initials: BN
authors.lastname: Zordoky
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.forename: Nasser
authors.initials: N
authors.lastname: Alsaleh
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: John M
authors.initials: JM
authors.lastname: Seubert
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000172:deficiency; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D013229:Stearic Acids / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; C120038:9,10-dihydroxy-12-octadecenoic acid; D001565:Benzoates; D002316:Cardiotonic Agents; D013229:Stearic Acids; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D014508:Urea; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D054648:Protein Phosphatase 2; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D015126:8,11,14-Eicosatrienoic Acid