高同型半胱氨酸血症中的表观遗传修饰：在糖尿病视网膜病变和年龄相关性黄斑变性中的潜在作用。
Epigenetic modifications in hyperhomocysteinemia: potential role in diabetic retinopathy and age-related macular degeneration.
作者信息
Elmasry Khaled, Mohamed Riyaz, Sharma Isha, Elsherbiny Nehal M, Liu Yutao, Al-Shabrawey Mohamed, Tawfik Amany
机构信息
Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA.
Department of Cellular Biology and Anatomy, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA.
出版信息
Oncotarget. 2018 Jan 29;9(16):12562-12590. doi: 10.18632/oncotarget.24333. eCollection 2018 Feb 27.
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 ( , and ), 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 mice retinas, whereas inhibition of HDAC and DNMT decreased Hcy-induced BRB dysfunction. MiRNA profiling detected 127 miRNAs in and 39 miRNAs in mice retinas, which were significantly differentially expressed compared to . 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.
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，对从缺乏胱硫醚β-合酶（ 、 和 ）导致同型半胱氨酸（Hcy）水平升高的三周龄小鼠分离的视网膜、人视网膜内皮细胞（HRECs）以及用或不用Hcy处理的人视网膜色素上皮细胞（ARPE - 19）进行了以下评估：（1）组蛋白脱乙酰酶（HDAC），（2）DNA甲基化（DNMT），以及（3）miRNA分析。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处理的视网膜色素上皮细胞释放的外泌体中的miRNA进行进一步比较。使用 Ingenuity Pathway Analysis对差异表达的miRNA的预测靶基因和相关途径进行进一步评估。HHcy显著增加了HRECs、ARPE - 19和 小鼠视网膜中的HDAC和DNMT活性，而抑制HDAC和DNMT可降低Hcy诱导的BRB功能障碍。miRNA谱分析在 小鼠视网膜中检测到127种miRNA，在 小鼠视网膜中检测到39种miRNA，与 相比它们有显著差异表达。miRNA途径分析表明它们参与HDAC和DNMT激活、内质网（ER）以及氧化应激、炎症、缺氧和血管生成途径。Hcy诱导的表观遗传修饰可能参与与HHcy相关的视网膜病变，如年龄相关性黄斑变性和糖尿病视网膜病变。
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