Abstract：
Long-chain polyunsaturated fatty acids (LCPUFAs) and their metabolites are closely related to neovascular eye diseases. However, the clinical significance of their oxylipins in retinal vein occlusion (RVO) remains inconclusive.
This case-control study aimed to explore metabolomic profiles of LCPUFA oxidation in RVO and to identify potential indicators for diagnosis and pathologic progression.
The plasma concentrations of ω-3 (n-3) and ω-6 (n-6) LCPUFA and their oxylipins in 44 adults with RVO and 36 normal controls were analyzed using ultraperformance liquid chromatography tandem mass spectrometry. Univariate analysis combined with principal component and orthogonal projections to latent structure discriminant analysis was used to screen differential metabolites. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of 5-oxo-eicosatetraenoic acids (ETE) on angiogenesis ex vivo. Tubule formation and wound healing assays were performed to verify its effects on human retinal microvascular endothelial cell functions.
Higher ω-6 and lower ω-3 LCPUFA plasma concentrations were measured in the adults with RVO compared with control (odds ratio [OR]: 2.34; 95% confidence interval [CI]: 1.42, 3.86; P < 0.001; OR: 0.28; 95% CI: 0.15, 0.51; P < 0.001). Metabolomic analysis revealed 20 LCPUFA and their oxylipins dysregulated in RVO, including increased arachidonic acid (ω-6, OR: 1.85; 95% CI: 1.18, 2.90; P < 0.001) and its lipoxygenase product 5-oxo-ETE (OR: 11.76; 95% CI: 3.73, 37.11; P < 0.001), as well as decreased docosahexaenoic acid (ω-3, OR: 0.13; 95% CI: 0.05, 0.33; P < 0.001). Interestingly, 5-oxo-ETE was downregulated in ischemic compared with nonischemic central RVO. Exogenous 5-oxo-ETE attenuated aortic ring and choroidal explant sprouting and inhibited tubule formation and migration of human retinal microvascular endothelial cells in a dose-dependent manner, possibly via suppressing the vascular endothelial growth factor signaling pathway.
The plasma concentrations of ω-6 and ω-3 LCPUFA and their oxylipins were associated with RVO. The ω-6 LCPUFA-derived metabolite 5-oxo-ETE was a potential marker of RVO development and progression.
This case-control study aimed to explore metabolomic profiles of LCPUFA oxidation in RVO and to identify potential indicators for diagnosis and pathologic progression.
The plasma concentrations of ω-3 (n-3) and ω-6 (n-6) LCPUFA and their oxylipins in 44 adults with RVO and 36 normal controls were analyzed using ultraperformance liquid chromatography tandem mass spectrometry. Univariate analysis combined with principal component and orthogonal projections to latent structure discriminant analysis was used to screen differential metabolites. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of 5-oxo-eicosatetraenoic acids (ETE) on angiogenesis ex vivo. Tubule formation and wound healing assays were performed to verify its effects on human retinal microvascular endothelial cell functions.
Higher ω-6 and lower ω-3 LCPUFA plasma concentrations were measured in the adults with RVO compared with control (odds ratio [OR]: 2.34; 95% confidence interval [CI]: 1.42, 3.86; P < 0.001; OR: 0.28; 95% CI: 0.15, 0.51; P < 0.001). Metabolomic analysis revealed 20 LCPUFA and their oxylipins dysregulated in RVO, including increased arachidonic acid (ω-6, OR: 1.85; 95% CI: 1.18, 2.90; P < 0.001) and its lipoxygenase product 5-oxo-ETE (OR: 11.76; 95% CI: 3.73, 37.11; P < 0.001), as well as decreased docosahexaenoic acid (ω-3, OR: 0.13; 95% CI: 0.05, 0.33; P < 0.001). Interestingly, 5-oxo-ETE was downregulated in ischemic compared with nonischemic central RVO. Exogenous 5-oxo-ETE attenuated aortic ring and choroidal explant sprouting and inhibited tubule formation and migration of human retinal microvascular endothelial cells in a dose-dependent manner, possibly via suppressing the vascular endothelial growth factor signaling pathway.
The plasma concentrations of ω-6 and ω-3 LCPUFA and their oxylipins were associated with RVO. The ω-6 LCPUFA-derived metabolite 5-oxo-ETE was a potential marker of RVO development and progression.
摘要：
背景：长链多不饱和脂肪酸（LCPUFA）及其代谢产物与新生血管性眼病密切相关。然而,它们的氧化脂素在视网膜静脉阻塞(RVO)中的临床意义仍不确定.
目的：本病例对照研究旨在探索RVO中LCPUFA氧化的代谢组学特征，并确定诊断和病理进展的潜在指标。
方法：采用超高效液相色谱-串联质谱法对44例RVO成人和36例正常对照者血浆中ω-3和ω-6LCPUFA及其氧化脂素水平进行分析。结合主成分和正交投影的单变量分析用于潜在结构判别分析来筛选差异代谢物。主动脉环和脉络膜外植体发芽测定法用于研究5-氧代-二十碳四烯酸（ETE）对离体血管生成的影响。进行小管形成和伤口愈合测定以验证其对人视网膜微血管内皮细胞(HRMEC)功能的影响。
结果：在患有RVO的成年人中测量到更高的ω-6和更低的ω-3LCPUFA血浆水平。控制(OR：2.34，95CI[1.42，3.86]，P<0.001；OR：0.28，95CI[0.15，0.51]，P<0.001)。代谢组学分析显示20LCPUFA及其氧化脂素在RVO中失调，包括花生四烯酸增加(ω-6，OR：1.85，95CI[1.18，2.90]，P<0.001）及其脂氧合酶产物5-氧代-ETE（OR：11.76，95CI[3.73，37.11]，P<0.001)，以及降低的二十二碳六烯酸（ω-3，OR：0.13，95CI[0.05，0.33]，P<0.001)。有趣的是,5-oxo-ETE在缺血性与非缺血性中枢RVO。外源性5-oxo-ETE减弱主动脉环和脉络膜外植体发芽，并以剂量依赖性方式抑制HRMEC的小管形成和迁移，可能通过抑制血管内皮生长因子信号通路。
结论：血浆ω-6和ω-3LCPUFA及其氧化脂素水平与RVO相关。ω-6LCPUFA衍生的代谢物5-氧代-ETE是RVO发育和进展的潜在标志物。
目的：本病例对照研究旨在探索RVO中LCPUFA氧化的代谢组学特征，并确定诊断和病理进展的潜在指标。
方法：采用超高效液相色谱-串联质谱法对44例RVO成人和36例正常对照者血浆中ω-3和ω-6LCPUFA及其氧化脂素水平进行分析。结合主成分和正交投影的单变量分析用于潜在结构判别分析来筛选差异代谢物。主动脉环和脉络膜外植体发芽测定法用于研究5-氧代-二十碳四烯酸（ETE）对离体血管生成的影响。进行小管形成和伤口愈合测定以验证其对人视网膜微血管内皮细胞(HRMEC)功能的影响。
结果：在患有RVO的成年人中测量到更高的ω-6和更低的ω-3LCPUFA血浆水平。控制(OR：2.34，95CI[1.42，3.86]，P<0.001；OR：0.28，95CI[0.15，0.51]，P<0.001)。代谢组学分析显示20LCPUFA及其氧化脂素在RVO中失调，包括花生四烯酸增加(ω-6，OR：1.85，95CI[1.18，2.90]，P<0.001）及其脂氧合酶产物5-氧代-ETE（OR：11.76，95CI[3.73，37.11]，P<0.001)，以及降低的二十二碳六烯酸（ω-3，OR：0.13，95CI[0.05，0.33]，P<0.001)。有趣的是,5-oxo-ETE在缺血性与非缺血性中枢RVO。外源性5-oxo-ETE减弱主动脉环和脉络膜外植体发芽，并以剂量依赖性方式抑制HRMEC的小管形成和迁移，可能通过抑制血管内皮生长因子信号通路。
结论：血浆ω-6和ω-3LCPUFA及其氧化脂素水平与RVO相关。ω-6LCPUFA衍生的代谢物5-氧代-ETE是RVO发育和进展的潜在标志物。
