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Salubrinal通过抑制CHOP-HIF1α-VEGF通路减轻视网膜新生血管形成。

Salubrinal attenuated retinal neovascularization by inhibiting CHOP-HIF1α-VEGF pathways.

作者信息

Hu Yaguang, Lu Xi, Xu Yue, Lu Lin, Yu Shanshan, Cheng Qiaochu, Yang Boyu, Tsui Ching-Kit, Ye Dan, Huang Jingjing, Liang Xiaoling

机构信息

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China.

Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.

出版信息

Oncotarget. 2017 Aug 24;8(44):77219-77232. doi: 10.18632/oncotarget.20431. eCollection 2017 Sep 29.

DOI:10.18632/oncotarget.20431
PMID:29100382
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5652775/
Abstract

Retinal neovascularization (RNV) related disease is the leading cause of irreversible blindness in the world. The aim of this study is to identify whether salubrinal could attenuate RNV by inhibiting CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP)- hypoxia inducible factors 1α (HIF1α) -vascular endothelial growth factor (VEGF) pathways in both mouse retinal microvascular endothelial cells (mRMECs) and oxygen-induced retinopathy (OIR) mouse model. After being treated with salubrinal (20μmol/L) or CHOP-siRNA, mRMECs were exposed to a hypoxia environment. OIR mice were intraperitoneally injected with salubrinal (0.5 mg/kg/day) from P12 to P17. With salubrinal or CHOP-siRNA treatment, the elevated CHOP protein and mRNA levels in hypoxia-induced mRMECs were significantly decreased. HIF1α-VEGF pathways were activated under hypoxia condition, then HIF1α protein was degraded and VEGF secretion was down-regulated after salubrinal or CHOP-siRNA treatment. In OIR mice, the areas of RNV were markedly decreased with salubrinal treatment. Moreover, elevated expressions of CHOP, HIF1α and VEGF in retinas of OIR mice were all reduced after salubrinal treatment. It suggested that salubrinal attenuated RNV in mRMECs and OIR mice by inhibiting CHOP-HIF1α-VEGF pathways and could be a potential therapeutic target for hypoxia-induced retinal microangiopathy.

摘要

视网膜新生血管（RNV）相关疾病是全球不可逆性失明的主要原因。本研究旨在确定沙芦比诺是否可通过抑制小鼠视网膜微血管内皮细胞（mRMECs）和氧诱导视网膜病变（OIR）小鼠模型中的CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP）-缺氧诱导因子1α（HIF1α）-血管内皮生长因子（VEGF）通路来减轻RNV。用沙芦比诺（20μmol/L）或CHOP-siRNA处理后，将mRMECs置于缺氧环境中。从P12至P17给OIR小鼠腹腔注射沙芦比诺（0.5mg/kg/天）。经沙芦比诺或CHOP-siRNA处理后，缺氧诱导的mRMECs中升高的CHOP蛋白和mRNA水平显著降低。在缺氧条件下HIF1α-VEGF通路被激活，经沙芦比诺或CHOP-siRNA处理后，HIF1α蛋白降解，VEGF分泌下调。在OIR小鼠中，沙芦比诺治疗后RNV面积明显减小。此外，沙芦比诺治疗后OIR小鼠视网膜中CHOP、HIF1α和VEGF的升高表达均降低。这表明沙芦比诺通过抑制CHOP-HIF1α-VEGF通路减轻了mRMECs和OIR小鼠中的RNV，可能是缺氧诱导的视网膜微血管病变的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/40d681009a66/oncotarget-08-77219-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/4a10a4ab61ad/oncotarget-08-77219-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/eee827cd0d78/oncotarget-08-77219-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/01106ade3466/oncotarget-08-77219-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/e53b74472203/oncotarget-08-77219-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/5466973d8904/oncotarget-08-77219-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/f31c3ecb082d/oncotarget-08-77219-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/a3382faff731/oncotarget-08-77219-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/40d681009a66/oncotarget-08-77219-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/4a10a4ab61ad/oncotarget-08-77219-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/eee827cd0d78/oncotarget-08-77219-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/01106ade3466/oncotarget-08-77219-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/e53b74472203/oncotarget-08-77219-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/5466973d8904/oncotarget-08-77219-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/f31c3ecb082d/oncotarget-08-77219-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/a3382faff731/oncotarget-08-77219-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e45/5652775/40d681009a66/oncotarget-08-77219-g008.jpg

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