Epigenetic modifications in hyperhomocysteinemia: potential role in diabetic retinopathy and age-related macular degeneration.
Epigenetic modifications in hyperhomocysteinemia: potential role in diabetic retinopathy and age-related macular degeneration.
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DOI：
10.18632/oncotarget.24333
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发表时间：
2018-02-27
期刊：
影响因子：
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通讯作者：
Tawfik A
中科院分区：
文献类型：
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作者：
Elmasry K;Mohamed R;Sharma I;Elsherbiny NM;Liu Y;Al-Shabrawey M;Tawfik A
为了研究高同型半胱氨酸血症 (HHcy) 诱导的表观遗传修饰作为血视网膜屏障 (BRB) 功能障碍的潜在机制，从因缺乏胱硫醚 β-合酶（cbs–/–、cbs+/– 和 cbs+/+）而导致同型半胱氨酸 (Hcy) 水平升高的三周龄小鼠、人视网膜内皮细胞 (HRECs) 和人视网膜中分离出视网膜评估用或不用 Hcy 处理的色素上皮细胞 (ARPE-19) 的 (1) 组蛋白脱乙酰酶 (HDAC)、(2) DNA 甲基化 (DNMT) 和 (3) miRNA 分析。进一步将 HHcy 小鼠中差异表达的 miRNA 与糖尿病小鼠视网膜 (STZ) 的 miRNA 分析以及 Hcy 处理的 RPE 释放的外泌体中的 miRNA 进行比较。使用 Ingenuity Pathway Analysis 进一步评估差异表达 miRNA 的预测靶基因和相关通路。 HHcy 显着增加 HREC、ARPE-19 和 cbs 小鼠视网膜中的 HDAC 和 DNMT 活性，而抑制 HDAC 和 DNMT 则减少 Hcy 诱导的 BRB 功能障碍。 miRNA 分析在 cbs+/– 小鼠视网膜中检测到 127 个 miRNA，在 cbs–/– 小鼠视网膜中检测到 39 个 miRNA，与 cbs+/+ 相比，这些 miRNA 的表达存在显着差异。 miRNA 通路分析显示它们参与 HDAC 和 DNMT 激活、内质网 (ER) 以及氧化应激、炎症、缺氧和血管生成通路。 Hcy 诱导的表观遗传修饰可能与 HHcy 相关的视网膜病变有关，例如年龄相关性黄斑变性和糖尿病视网膜病变。
To study Hyperhomocysteinemia (HHcy)-induced epigenetic modifications as potential mechanisms of blood retinal barrier (BRB) dysfunction, retinas isolated from three- week-old mice with elevated level of Homocysteine (Hcy) due to lack of the enzyme cystathionine β-synthase (cbs–/–, cbs+/– and cbs+/+), human retinal endothelial cells (HRECs), and human retinal pigmented epithelial cells (ARPE-19) treated with or without Hcy were evaluated for (1) histone deacetylases (HDAC), (2) DNA methylation (DNMT), and (3) miRNA analysis. Differentially expressed miRNAs in mice with HHcy were further compared with miRNA analysis of diabetic mice retinas (STZ) and miRNAs within the exosomes released from Hcy-treated RPEs. Differentially expressed miRNAs were further evaluated for predicted target genes and associated pathways using Ingenuity Pathway Analysis. HHcy significantly increased HDAC and DNMT activity in HRECs, ARPE-19, and cbs mice retinas, whereas inhibition of HDAC and DNMT decreased Hcy-induced BRB dysfunction. MiRNA profiling detected 127 miRNAs in cbs+/– and 39 miRNAs in cbs–/– mice retinas, which were significantly differentially expressed compared to cbs+/+. MiRNA pathway analysis showed their involvement in HDAC and DNMT activation, endoplasmic reticulum (ER), and oxidative stresses, inflammation, hypoxia, and angiogenesis pathways. Hcy-induced epigenetic modifications may be involved in retinopathies associated with HHcy, such as age-related macular degeneration and diabetic retinopathy.