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Cytochrome P450 Oxidase 2C Inhibition Adds to-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization

Artikel i vetenskaplig tidskrift
Författare Y. Gong
Z. J. Fu
M. L. Edin
C. H. Liu
Z. X. Wang
Z. Shao
T. W. Fredrick
N. J. Saba
P. C. Morss
S. B. Burnim
S. S. Meng
F. B. Lih
K. S. S. Lee
E. P. Moran
J. P. Sangiovanni
Ann Hellström
B. D. Hammock
D. C. Zeldin
L. E. H. Smith
Publicerad i Arteriosclerosis Thrombosis and Vascular Biology
Volym 36
Nummer/häfte 9
Sidor 1919-1927
ISSN 1079-5642
Publiceringsår 2016
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap och rehabilitering
Sidor 1919-1927
Språk en
Länkar dx.doi.org/10.1161/atvbaha.116.3075...
Ämnesord arachidonic acid, choroidal neovascularization, CYP2C inhibitor, diabetic retinopathy, docosahexaenoic acid, soluble epoxide hydrolase, endothelial growth-factor, leukotriene, cyslt(1) receptor, macular degeneration, diabetic-retinopathy, mouse, angiogenesis, montelukast, prematurity, metabolites, Hematology, Cardiovascular System & Cardiology
Ämneskategorier Klinisk medicin

Sammanfattning

Objective Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of -3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but -3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of -3 LCPUFA on neovascular eye diseases. Approach and Results The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of -3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and -3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of -3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a -3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C -3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected -3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. Conclusions Inhibition of CYP2C activity adds to the protective effects of -3 LCPUFA on pathological retinal neovascularization and CNV.

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