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Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis.

ABSTRACT: Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)? agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP)2C with higher affinity than to PPAR?. CYP2C metabolizes ?-3 long-chain polyunsaturated fatty acids (LCPUFAs). While ?-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both ?-3 and ?-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C ?-3 LCPUFA (and ?-6 LCPUFA) pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPAR?-/-mice and augmented ?-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic ?-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPAR?. Fenofibrate augmented the overall protective effects of ?-3 LCPUFAs on neovascular eye diseases.

SUBMITTER: Gong Y

PROVIDER: S-EPMC5264653 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis.

Gong Yan Y Shao Zhuo Z Fu Zhongjie Z Edin Matthew L ML Sun Ye Y Liegl Raffael G RG Wang Zhongxiao Z Liu Chi-Hsiu CH Burnim Samuel B SB Meng Steven S SS Lih Fred B FB SanGiovanni John Paul JP Zeldin Darryl C DC Hellström Ann A Smith Lois E H LEH

EBioMedicine 20160930

Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)α agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP)2C with higher affinity than to PPARα. CYP2C metabolizes ω-3 ...[more]

PMID: 27720395

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Project description:This is the largest study describing the role of P450 epoxygenase metabolites in septic shock in humans and suggests a novel therapeutic target.ObjectivesOxylipins are oxidative breakdown products of cell membrane fatty acids. Animal models have demonstrated that oxylipins generated by the P450 epoxygenase pathway may be implicated in septic shock pathology. However, these mediators are relatively unexplored in humans with septic shock. We aimed to determine if there were patterns of oxylipins that were associated with 28-day septic shock mortality and organ dysfunction.DesignRetrospective analysis of samples collected during the Vasopressin versus Norepinephrine as Initial Therapy in Septic Shock trial.SettingICUs in the United Kingdom.ParticipantsAdults recruited within 6 hours of onset of septic shock.Main outcomes and measuresOxylipin profiling was performed on 404 serum samples from 152 patients using liquid chromatography-mass spectrometry.ResultsNonsurvivors were found to have higher levels of 14,15-dihydroxyeicosatrienoic acid (DHET) at baseline than survivors (p = 0.02). Patients with 14,15-DHET levels above the lower limit of quantification of the assay were more likely to die than patients with levels below this limit (hazard ratio, 2.3; 95% CI, 1.2-4.5). Patients with measurable 14,15-DHET had higher levels of organ dysfunction and fewer renal failure-free days than those in whom it was unmeasurable. Considering samples collected over the first week of intensive care stay, measurable levels of DHET species were associated with higher daily Sequential Organ Failure Assessment scores that appeared to be accounted for predominantly by the liver component. Measurable 14,15-DHET showed positive correlation with bilirubin (r s = 0.38; p < 0.001) and lactate (r s = 0.27; p = 0.001).Conclusions and relevanceThe P450 epoxygenase-derived DHET species of oxylipins were associated with organ, particularly liver, dysfunction in septic shock and 14,15-DHET was associated with septic shock mortality. These results support further investigation into the role of the P450 epoxygenase-derived oxylipins in sepsis and suggest that this pathway may offer a novel therapeutic strategy in septic shock.

Dataset Information

Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis.

Publications

Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis.

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