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PMID: 21697548 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology ·Vol. 25 ·No. 10 ·2011-10-00 ·Pages 3436-47

Edin ML, Wang Z, Bradbury JA, Graves JP, Lih FB, DeGraff LM, Foley JF, Torphy R, Ronnekleiv OK, Tomer KB, Lee CR, Zeldin DC

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.

MeSH Terms
Animals Aryl Hydrocarbon Hydroxylases/genetics,metabolism Cytochrome P-450 CYP2C8 Cytochrome P-450 CYP2J2 Cytochrome P-450 Enzyme System/genetics,metabolism Eicosanoids/metabolism Endothelium, Vascular/metabolism Epoxide Hydrolases/genetics,metabolism Heart/physiology Humans Mice Mice, Transgenic Oleic Acids/metabolism Promoter Regions, Genetic Receptor Protein-Tyrosine Kinases/genetics,metabolism Receptor, TIE-2 Reperfusion Injury/metabolism
Chemicals
CYP2J2 protein, human Eicosanoids Oleic Acids Cytochrome P-450 Enzyme System Aryl Hydrocarbon Hydroxylases CYP2C8 protein, human Cytochrome P-450 CYP2C8 Cytochrome P-450 CYP2J2 Receptor Protein-Tyrosine Kinases Receptor, TIE-2 Tek protein, mouse Epoxide Hydrolases
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Edin Matthew L
Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Wang Zhongjing
Bradbury J Alyce
Graves Joan P
Lih Fred B
DeGraff Laura M
Foley Julie F
Torphy Robert
Ronnekleiv Oline K
Tomer Kenneth B
Lee Craig R
Zeldin Darryl C
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Article Info
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Abbr.
FASEB J
ISSN
1530-6860
DOI
10.1096/fj.11-188300
Published
2011-10-00
Epub
2011-00-22
Pages
3436-47
Language
English
Region
United States
NLM ID
8804484
PMCID
PMC3177568
Subset
IM
Grants
NIGMS NIH HHS · R01 GM088199-02 · United States
Intramural NIH HHS · Z01 ES025034 · United States
NIGMS NIH HHS · R01 GM088199-03 · United States
NIGMS NIH HHS · R01 GM088199 · United States
Intramural NIH HHS · Z01 ES050167 · United States
External Links
PubMed source DOI: 10.1096/fj.11-188300 PMC Full Text View journal details
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