Metabolomic Profiling of Long-Chain Polyunsaturated Fatty Acid Oxidation in Adults with Retinal Vein Occlusion: A Case-Control Study

Background: 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.Objectives: This case-control study aimed to explore metabolomic profiles of LCPUFA oxidation in RVO and to identify potential indicators for diagnosis and pathologic progression.Methods: The plasma concentrations of omega-3 (n-3) and omega-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.Results: Higher omega-6 and lower omega-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 (omega-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 (omega-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.Conclusions: The plasma concentrations of omega-6 and omega-3 LCPUFA and their oxylipins were associated with RVO. The omega-6 LCPUFA-derived metabolite 5-oxo-ETE was a potential marker of RVO development and progression.

Automated summary

This study analyzed the differences in plasma concentrations of LCPUFAs and their oxidized products between patients with RVO and normal controls, and found that RVO patients had higher levels of omega-6 and lower levels of omega-3 in their plasma. Metabolomic analysis also revealed 20 dysregulated LCPUFAs and their oxidized products in RVO. Additionally, the study identified 5-oxo-ETE as a potential marker for RVO development and progression.