中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 1132-1138.doi: 10.4103/1673-5374.355819

• 原著:视神经损伤修复保护与再生 • 上一篇    下一篇

piR-1245是视网膜新生血管形成的治疗靶点

  

  • 出版日期:2023-05-15 发布日期:2022-11-01
  • 基金资助:
    中国国家自然科学基金项目（81570866）

Mechanism of piR-1245/PIWI-like protein-2 regulating Janus kinase-2/signal transducer and activator of transcription-3/vascular endothelial growth factor signaling pathway in retinal neovascularization

Yong Yu, Li-Kun Xia, Yu Di, Qing-Zhu Nie, Xiao-Long Chen*   

  1. Department of Ophthalmology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
  • Online:2023-05-15 Published:2022-11-01
  • Contact: Xiao-Long Chen, MD, chenxl@sj-hospital.org.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81570866 (to XLC).

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摘要：

抑制视网膜新生血管形成是视网膜相关疾病治疗的主要策略，但尚无有效的治疗方法。piRNA是一种小的非编码RNA，可通过与PIWI样蛋白的相互作用参与多种生命活动。实验首先发现缺氧环境培养的人视网膜内皮细胞中piR-1245及其相互作用的蛋白PIWIL2的表达明显增加，且细胞凋亡、迁移、管形成以及增殖能力明显增强，而敲除细胞中的piR-1245，则会抑制上述现象。进而以p-JAK2 激活剂进行干预，发现piR-1245是通过JAK2/STAT3通路影响缺氧诱导因子 1α和血管内皮生长因子表达而实现的。进一步体内实验中，将7d龄新生小鼠于75 ± 2%高氧环境中饲养5d，而后敲低视网膜中的piR-1245。结果发现视网膜新生血管数量减少，炎症相关蛋白表达被抑制，视网膜细胞凋亡减少， JAK2/STAT3通路受到抑制，缺氧诱导因子 1α和血管内皮生长因子表达降低。在玻璃体腔注射JAK2抑制剂JAK2/TYK2-IN-1 也可抑制小鼠视网膜新生血管，并诱导JAK2/STAT3通路蛋白以及缺氧诱导因子 1α和血管内皮生长因子的低表达。上述发现表明piR-1245可激活 JAK2/STAT3 通路并调节缺氧诱导因子 1α和血管内皮生长因子表达，进而促进视网膜新生血管形成，因而可作为视网膜新生血管形成的新治疗靶点。

https://orcid.org/0000-0001-7653-7515 (Xiao-Long Chen)

关键词: 氧化损伤, 视网膜病变, 非编码RNA, 血管生成, PIWI相互作用的RNA, 缺氧, 人视网膜内皮细胞, 缺氧诱导因子1α, 白细胞介素1β, 细胞迁移

Abstract: Inhibiting retinal neovascularization is the optimal strategy for the treatment of retina-related diseases, but there is currently no effective treatment for retinal neovascularization. P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) is a type of small non-coding RNA implicated in a variety of diseases. In this study, we found that the expression of piR-1245 and the interacting protein PIWIL2 were remarkably increased in human retinal endothelial cells cultured in a hypoxic environment, and cell apoptosis, migration, tube formation and proliferation were remarkably enhanced in these cells. Knocking down piR-1245 inhibited the above phenomena. After intervention by a p-JAK2 activator, piR-1245 decreased the expression of hypoxia inducible factor-1α and vascular endothelial growth factor through the JAK2/STAT3 pathway. For in vivo analysis, 7-day-old newborn mice were raised in 75 ± 2% hyperoxia for 5 days and then piR-1245 in the retina was knocked down. In these mice, the number of newly formed vessels in the retina was decreased, the expressions of inflammation-related proteins were reduced, the number of apoptotic cells in the retina was decreased, the JAK2/STAT3 pathway was inhibited, and the expressions of hypoxia inducible factor-1α and vascular endothelial growth factor were decreased. Injection of the JAK2 inhibitor JAK2/TYK2-IN-1 into the vitreous cavity inhibited retinal neovascularization in mice and reduced expression of hypoxia inducible factor-1α and vascular endothelial growth factor. These findings suggest that piR-1245 activates the JAK2/STAT3 pathway, regulates the expression of hypoxia inducible factor-1α and vascular endothelial growth factor, and promotes retinal neovascularization. Therefore, piR-1245 may be a new therapeutic target for retinal neovascularization. 

Key words: angiogenesis, human retinal endothelial cells, hypoxia inducible factor-1α, hypoxia, interleukin-1β, migration, non-coding RNA, oxygen-induced injury, PIWI-interacting RNA, retinopathy