Guo Ju, Zhou Pengyi, Liu Zhenhui, Dai Fangfang, Pan Meng, An Guangqi, Han Jinfeng, Du Liping, Jin Xuemin
Department of Ophthalmology, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
People's Hospital of Zhengzhou University and Henan Eye Institute, Zhengzhou, China.
Front Pharmacol. 2021 Dec 6;12:781276. doi: 10.3389/fphar.2021.781276. eCollection 2021.
Vascular endothelial growth factor-A (VEGF-A) is an important pathogenic factor in proliferative diabetic retinopathy (PDR), and aflibercept (Eylea) is one of the widely used anti-VEGF agents. This study investigated the microRNA (miRNA) profiles in the vitreous of 5 idiopathic macular hole patients (non-diabetic controls), 5 untreated PDR patients (no-treatment group), and 5 PDR patients treated with intravitreal aflibercept injection (treatment group). Next-generation sequencing was performed to determine the miRNA profiles. Deregulated miRNAs were validated with quantitative real-time PCR (qRT-PCR) in another cohort. The mRNA profile data (GSE160310) of PDR patients were retrieved from the Gene Expression Omnibus (GEO) database. The function of differentially expressed miRNAs and mRNAs was annotated by bioinformatic analysis and literature study. Twenty-nine miRNAs were significantly dysregulated in the three groups, of which 19,984 target mRNAs were predicted. Hsa-miR-3184-3p, hsa-miR-24-3p, and hsa-miR-197-3p were validated to be remarkably upregulated in no-treatment group versus controls, and significantly downregulated in treatment group versus no-treatment group. In the GSE160310 profile, 204 deregulated protein-coding mRNAs were identified, and finally 179 overlapped mRNAs between the 19,984 target mRNAs and 204 deregulated mRNAs were included for further analysis. Function analysis provided several roles of aflibercept-induced miRNAs, promoting the alternation of drug sensitivity or resistance-related mRNAs, and regulating critical mRNAs involved in angiogenesis and retinal fibrosis. Hsa-miR-3184-3p, hsa-miR-24-3p, and hsa-miR-197-3p were highly expressed in PDR patients, and intravitreal aflibercept injection could reverse this alteration. Intravitreal aflibercept injection may involve in regulating cell sensitivity or resistance to drug, angiogenesis, and retinal fibrosis.
血管内皮生长因子 -A（VEGF -A）是增殖性糖尿病视网膜病变（PDR）中的一个重要致病因素，阿柏西普（Eylea）是广泛使用的抗VEGF药物之一。本研究调查了5例特发性黄斑裂孔患者（非糖尿病对照组）、5例未经治疗的PDR患者（未治疗组）和5例接受玻璃体内注射阿柏西普治疗的PDR患者（治疗组）玻璃体中的微小RNA（miRNA）谱。采用下一代测序技术确定miRNA谱。在另一队列中用定量实时PCR（qRT-PCR）验证失调的miRNA。从基因表达综合数据库（GEO）中检索PDR患者的mRNA谱数据（GSE160310）。通过生物信息学分析和文献研究注释差异表达的miRNA和mRNA的功能。三组中有29个miRNA显著失调，预测其中有19984个靶mRNA。验证发现，与对照组相比，hsa-miR-3184-3p、hsa-miR-24-3p和hsa-miR-197-3p在未治疗组中显著上调，与未治疗组相比，在治疗组中显著下调。在GSE160310谱中，鉴定出204个失调的蛋白质编码mRNA，最终在19984个靶mRNA和204个失调mRNA之间纳入179个重叠mRNA进行进一步分析。功能分析揭示了阿柏西普诱导的miRNA的多种作用，促进药物敏感性或耐药性相关mRNA的改变，并调节参与血管生成和视网膜纤维化的关键mRNA。hsa-miR-3184-3p、hsa-miR-24-3p和hsa-miR-197-3p在PDR患者中高表达，玻璃体内注射阿柏西普可逆转这种改变。玻璃体内注射阿柏西普可能参与调节细胞对药物的敏感性或耐药性、血管生成和视网膜纤维化。
