Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis
Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis
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DOI：
10.2337/db16-1035
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发表时间：
2017-07-01
期刊：
影响因子：
7.7
通讯作者：
Arboleda-Velasquez, Joseph F.
中科院分区：
文献类型：
--
作者：
Lam, Jonathan D.;Oh, Daniel J.;Arboleda-Velasquez, Joseph F.
糖尿病性视网膜病变（PDR）是发达国家工作成年人群中常见的致盲原因，并影响1型和2型糖尿病患者。我们通过转录组学分析鉴定了Runt相关转录因子1（RUNX 1）作为一种在从人PDR纤维血管膜（FVM）获得的CD 31（+）血管内皮细胞中上调的基因。使用人视网膜微血管内皮细胞（HRMEC）的体外研究显示，响应于高葡萄糖，RUNX 1 RNA和蛋白表达增加，而RUNX 1抑制降低HRMEC迁移，增殖和管形成。RUNX 1的免疫组织化学染色显示，在患有氧诱导视网膜病变的小鼠视网膜中，患者来源的FVM和血管生成簇的血管中存在反应性，这表明RUNX 1上调是异常视网膜血管生成的标志。用Ro 5 -3335小分子抑制RUNX 1活性导致氧诱导的视网膜病变中新生血管簇的显著减少，支持靶向RUNX 1在异常视网膜血管生成中的可行性。
Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world's working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31(+) vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5-3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.