Document Detail

Cytochrome P450 2C8 ω3-long-chain polyunsaturated fatty acid metabolites increase mouse retinal pathologic neovascularization--brief report.
MedLine Citation:
PMID:  24458713     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Regulation of angiogenesis is critical for many diseases. Specifically, pathological retinal neovascularization, a major cause of blindness, is suppressed with dietary ω3-long-chain polyunsaturated fatty acids (ω3LCPUFAs) through antiangiogenic metabolites of cyclooxygenase and lipoxygenase. Cytochrome P450 epoxygenases (CYP2C8) also metabolize LCPUFAs, producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to transdihydrodiols. The effect of these enzymes and their metabolites on neovascularization is unknown.
APPROACH AND RESULTS: The mouse model of oxygen-induced retinopathy was used to investigate retinal neovascularization. We found that CYP2C (localized in wild-type monocytes/macrophages) is upregulated in oxygen-induced retinopathy, whereas sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a ω3LCPUFA-enriched diet, retinal neovascularization increases in Tie2-driven human-CYP2C8-overexpressing mice (Tie2-CYP2C8-Tg), associated with increased plasma 19,20-epoxydocosapentaenoic acid and retinal epoxide:diol ratio. 19,20-Epoxydocosapentaenoic acids and the epoxide:diol ratio are decreased with overexpression of sEH (Tie2-sEH-Tg). Overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls. The proangiogenic role in retina of CYP2C8 with both ω3LCPUFA and ω6LCPUFA and antiangiogenic role of sEH in ω3LCPUFA metabolism were corroborated in aortic ring assays.
CONCLUSIONS: Our results suggest that CYP2C ω3LCPUFA metabolites promote retinal pathological angiogenesis. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization.
Zhuo Shao; Zhongjie Fu; Andreas Stahl; Jean-Sébastien Joyal; Colman Hatton; Aimee Juan; Christian Hurst; Lucy Evans; Zhenghao Cui; Dorothy Pei; Yan Gong; Dan Xu; Katherine Tian; Hannah Bogardus; Matthew L Edin; Fred Lih; Przemyslaw Sapieha; Jing Chen; Dipak Panigrahy; Ann Hellstrom; Darryl C Zeldin; Lois E H Smith
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2014-01-23
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  34     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2014 Mar 
Date Detail:
Created Date:  2014-02-20     Completed Date:  2014-04-16     Revised Date:  2014-11-04    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  581-6     Citation Subset:  IM    
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MeSH Terms
Arachidonic Acid / metabolism
Aryl Hydrocarbon Hydroxylases / genetics,  metabolism*
Cell Hypoxia
Dietary Fats / pharmacokinetics
Docosahexaenoic Acids / metabolism
Eicosapentaenoic Acid / metabolism
Epoxide Hydrolases / deficiency,  genetics,  physiology
Eye Proteins / metabolism
Fatty Acids, Omega-3 / administration & dosage,  classification,  pharmacokinetics,  toxicity*
Fatty Acids, Unsaturated / administration & dosage,  pharmacokinetics
Lipoxygenase / metabolism
Macrophages / enzymology*
Mice, Inbred C57BL
Mice, Transgenic
Monocytes / enzymology*
Oxygen / toxicity
Prostaglandin-Endoperoxide Synthases / metabolism
RNA, Messenger / biosynthesis
Receptor, TIE-2 / genetics
Recombinant Fusion Proteins / metabolism
Retinal Neovascularization / chemically induced*,  prevention & control
Grant Support
EY017017/EY/NEI NIH HHS; EY022275/EY/NEI NIH HHS; P01HD18655/HD/NICHD NIH HHS; R01 CA148633/CA/NCI NIH HHS; R01 EY017017/EY/NEI NIH HHS; R01 EY022275/EY/NEI NIH HHS; R01CA148633-01A4/CA/NCI NIH HHS; //Canadian Institutes of Health Research
Reg. No./Substance:
0/Dietary Fats; 0/Eye Proteins; 0/Fatty Acids, Omega-3; 0/Fatty Acids, Unsaturated; 0/RNA, Messenger; 0/Recombinant Fusion Proteins; 25167-62-8/Docosahexaenoic Acids; 27YG812J1I/Arachidonic Acid; AAN7QOV9EA/Eicosapentaenoic Acid; EC; EC Hydrocarbon Hydroxylases; EC protein, human; EC protein, mouse; EC Synthases; EC 2.7.1.-/Tek protein, mouse; EC, TIE-2; EC 3.3.2.-/Epoxide Hydrolases; EC protein, mouse; S88TT14065/Oxygen

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