title: Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart.
abstract: Cytochrome P450 (CYP) epoxygenases CYP2C8 and CYP2J2 generate epoxyeicosatrienoic acids (EETs) from arachidonic acid. Mice with expression of CYP2J2 in cardiomyocytes (αMHC-CYP2J2 Tr) or treated with synthetic EETs have increased functional recovery after ischemia/reperfusion (I/R); however, no studies have examined the role of cardiomyocyte- vs. endothelial-derived EETs or compared the effects of different CYP epoxygenase isoforms in the ischemic heart. We generated transgenic mice with increased endothelial EET biosynthesis (Tie2-CYP2C8 Tr and Tie2-CYP2J2 Tr) or EET hydrolysis (Tie2-sEH Tr). Compared to wild-type (WT), αMHC-CYP2J2 Tr hearts showed increased recovery of left ventricular developed pressure (LVDP) and decreased infarct size after I/R. In contrast, LVDP recovery and infarct size were unchanged in Tie2-CYP2J2 Tr and Tie2-sEH Tr hearts. Surprisingly, compared to WT, Tie2-CYP2C8 Tr hearts had significantly reduced LVDP recovery (from 21 to 14%) and increased infarct size after I/R (from 51 to 61%). Tie2-CYP2C8 Tr hearts also exhibited increased reactive oxygen species (ROS) generation, dihydroxyoctadecenoic acid (DiHOME) formation, and coronary resistance after I/R. ROS scavengers and CYP2C8 inhibition reversed the detrimental effects of CYP2C8 expression in Tie2-CYP2C8 Tr hearts. Treatment of WT hearts with 250 nM 9,10-DiHOME decreased LVDP recovery compared to vehicle (16 vs. 31%, respectively) and increased coronary resistance after I/R. These data demonstrate that increased ROS generation and enhanced DiHOME synthesis by endothelial CYP2C8 impair functional recovery and mask the beneficial effects of increased EET production following I/R.
authors.affiliation: Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.forename: Zhongjing
authors.initials: Z
authors.lastname: Wang
authors.forename: J Alyce
authors.initials: JA
authors.lastname: Bradbury
authors.forename: Joan P
authors.initials: JP
authors.lastname: Graves
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.forename: Julie F
authors.initials: JF
authors.lastname: Foley
authors.forename: Robert
authors.initials: R
authors.lastname: Torphy
authors.forename: Oline K
authors.initials: OK
authors.lastname: Ronnekleiv
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Tomer
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D065727:Cytochrome P-450 CYP2C8; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009829:Oleic Acids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: C000717350:CYP2J2 protein, human; D015777:Eicosanoids; D009829:Oleic Acids; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000090762:Cytochrome P-450 CYP2J2; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D004851:Epoxide Hydrolases