Cytochrome P450 2C8 ω3-long-chain polyunsaturated fatty acid metabolites increase mouse retinal pathologic neovascularization--brief report.
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.


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.
From the Department of Ophthalmology, Boston Children's Hospital (Z.S., Z.F., J.-S.J., C. Hatton, A.J., C. Hurst, L.E., Z.C., D.P., Y.G., D.X., K.T., H.B., J.C., L.E.H.S.) and Department of Pathology, Beth Israel Deaconess Medical Center (D.P.), Harvard Medical School, Boston, MA; University Eye Hospital Freiburg, Freiburg, Germany (A.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, NC (M.L.E., F.L., D.C.Z.); Department of Ophthalmology, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec, Canada (P.S.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.).
Zhuo
Z
Shao
Zhongjie
Z
Fu
Andreas
A
Stahl
Jean-Sébastien
JS
Joyal
Colman
C
Hatton
Aimee
A
Juan
Christian
C
Hurst
Lucy
L
Evans
Zhenghao
Z
Cui
Dorothy
D
Pei
Yan
Y
Gong
Dan
D
Xu
Katherine
K
Tian
Hannah
H
Bogardus
Matthew L
ML
Edin
Fred
F
Lih
Przemyslaw
P
Sapieha
Jing
J
Chen
Dipak
D
Panigrahy
Ann
A
Hellstrom
Darryl C
DC
Zeldin
Lois E H
LE
Smith
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D015687:Cell Hypoxia; D065727:Cytochrome P-450 CYP2C8; D004041:Dietary Fats / Q000493:pharmacokinetics; D004281:Docosahexaenoic Acids / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005136:Eye Proteins / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008084:Lipoxygenase / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000201:enzymology*; D010100:Oxygen / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D042787:Receptor, TIE-2 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015861:Retinal Neovascularization / Q000139:chemically induced* / Q000517:prevention & control
D004041:Dietary Fats; D005136:Eye Proteins; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid; D008084:Lipoxygenase; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C587823:CYP2C8 protein, mouse; D065727:Cytochrome P-450 CYP2C8; D011451:Prostaglandin-Endoperoxide Synthases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D004851:Epoxide Hydrolases; C543485:EPHX1 protein, mouse; D010100:Oxygen
angiogenesis factor; cytochrome P450 CYP2C8 (human); pathologic neovascularization