Department of Ophthalmology, University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Cells. 2022 Nov 4;11(21):3494. doi: 10.3390/cells11213494.
Cytochrome P450 (CYP) gene mutations are a common predisposition associated with glaucoma. Although the molecular mechanisms are largely unknown, omega-3 polyunsaturated fatty acids (ω-3 PUFA) and their CYP-derived bioactive mediators play crucial roles in the ocular system. Here, we elucidated the proteome and cell-signalling alterations attributed to the main human gene deficiency using a homologous murine model (), and unravelled the effects of acute ω-3 PUFA supplementation in two ocular vascular beds comprising the retrobulbar ophthalmic artery (OA) and retina (R). Male mice (KO) and their floxed littermates (WT) were gavaged daily for 7 days with 0.01 mL/g of ω-3 PUFA composed of menhaden fish oil. Another group in respective strains served as vehicle-treated controls. OA and R were isolated at day 8 post-treatment ( = 9/group) and subjected to mass spectrometry (MS)-based proteomics and bioinformatics analyses. resulted in significant detrimental proteome changes associated with compromised vascular integrity and degeneration in the OA and R, respectively. However, notable changes in the OA after ω-3 PUFA intake were associated with the maintenance of intercellular junctional and endothelial cell functions, as well as activation of the fatty acid metabolic pathway in the KO mice. Conversely, ω-3 PUFA supplementation profoundly influenced the regulation of a large majority of retinal proteins involved in the preservation of neuronal and phototransduction activities in WT mice, namely synaptophysin, phosducin and guanylate cyclase-1, while significantly abrogating degenerative processes in the KO mice the regulation of, namely, synaptotagmin-1 and beta-crystallin B2. In gist, this study demonstrated that dietary supplementation with ω-3 PUFA for a short period of seven days regulated specific neuro-vasculoprotective mechanisms to preserve the functionality of the OA and R in the absence of Cyp2c44. The potential adjunct use of ω-3 PUFA for glaucoma therapy needs further investigation.
细胞色素 P450（CYP）基因突变是与青光眼相关的常见易感性因素。尽管其分子机制在很大程度上尚未阐明，但ω-3 多不饱和脂肪酸（ω-3 PUFA）及其 CYP 衍生的生物活性介质在眼系统中发挥着至关重要的作用。在这里，我们使用同源鼠模型（）阐明了主要人类基因缺陷相关的蛋白质组和细胞信号改变，并揭示了急性ω-3 PUFA 补充对两个包含球后眶内动脉（OA）和视网膜（R）的眼血管床的影响。雄性 KO 小鼠（KO）及其 floxed 同窝仔鼠（WT）每天用 0.01 mL/g 的ω-3 PUFA 灌胃 7 天，ω-3 PUFA 由鲱鱼油组成。各自品系中的另一组作为载体处理对照。在治疗后第 8 天（每组 n=9）分离 OA 和 R，并进行基于质谱（MS）的蛋白质组学和生物信息学分析。结果表明，OA 和 R 的血管完整性受损和退化分别与显著的有害蛋白质组变化相关。然而，KO 小鼠在摄入 ω-3 PUFA 后 OA 发生的显著变化与细胞间连接和内皮细胞功能的维持以及脂肪酸代谢途径的激活有关。相反，ω-3 PUFA 补充对 WT 小鼠中涉及神经元和光转导活动保护的大多数视网膜蛋白的调节产生了深远的影响，即突触小体蛋白、磷蛋白和鸟苷酸环化酶-1，同时在 KO 小鼠中显著阻止了退化过程，即突触结合蛋白-1 和β-晶体蛋白 B2。总之，本研究表明，在没有 Cyp2c44 的情况下，短期（7 天）ω-3 PUFA 饮食补充调节了特定的神经血管保护机制，以维持 OA 和 R 的功能。ω-3 PUFA 用于治疗青光眼的潜在辅助作用需要进一步研究。
