Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization.
Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization.
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DOI：
10.1016/j.omtn.2017.01.004
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发表时间：
2017-03-17
期刊：
影响因子：
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通讯作者：
Ishibashi T
中科院分区：
文献类型：
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作者：
Nakama T;Yoshida S;Ishikawa K;Kubo Y;Kobayashi Y;Zhou Y;Nakao S;Hisatomi T;Ikeda Y;Takao K;Yoshikawa K;Matsuda A;Ono J;Ohta S;Izuhara K;Kudo A;Sonoda KH;Ishibashi T
视网膜缺血引起的视网膜新生血管（NV）是缺血性视网膜疾病患者视力损害的主要原因之一。我们最近报道，骨膜蛋白（POSTIN）可能在视网膜前纤维血管膜的发展中发挥作用，但其在视网膜NV中的作用尚未确定。本研究的目的是检测POR4在氧诱导的视网膜NV小鼠模型的缺血视网膜中的表达。我们还使用培养的Postn KO小鼠和人视网膜内皮细胞（HRECs）研究了POR4对视网膜NV的功能。此外，我们使用了一种新的RNAi剂，NK0144，其靶向POR4，以确定其对视网膜NV发展的影响。我们的研究结果表明，在缺血视网膜的血管内皮细胞，周细胞和M2巨噬细胞中，POR4的表达增加。PO4可通过整合素αvβ3介导Akt磷酸化促进缺血诱导的视网膜NV。NK0144在体内和体外对视网膜前病变NV的抑制作用均大于经典的双链siRNA。这些发现表明POR4和视网膜NV之间存在因果关系，并表明玻璃体内注射NK0144对视网膜新生血管性疾病具有潜在的治疗作用。
Retinal neovascularization (NV) due to retinal ischemia remains one of the principal causes of vision impairment in patients with ischemic retinal diseases. We recently reported that periostin (POSTN) may play a role in the development of preretinal fibrovascular membranes, but its role in retinal NV has not been determined. The purpose of this study was to examine the expression of POSTN in the ischemic retinas of a mouse model of oxygen-induced retinal NV. We also studied the function of POSTN on retinal NV using Postn KO mice and human retinal endothelial cells (HRECs) in culture. In addition, we used a novel RNAi agent, NK0144, which targets POSTN to determine its effect on the development of retinal NV. Our results showed that the expression of POSTN was increased in the vascular endothelial cells, pericytes, and M2 macrophages in ischemic retinas. POSTN promoted the ischemia-induced retinal NV by Akt phosphorylation through integrin αvβ3. NK0144 had a greater inhibitory effect than canonical double-stranded siRNA on preretinal pathological NV in vivo and in vitro. These findings suggest a causal relationship between POSTN and retinal NV, and indicate a potential therapeutic role of intravitreal injection of NK0144 for retinal neovascular diseases.