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年轻和老年自发性高血压大鼠之间差异 microRNA 表达谱和生物信息学分析。

Differential microRNA expression profiles and bioinformatics analysis between young and aging spontaneously hypertensive rats.

机构信息

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.

Department of Cardiology, Zoucheng Hospital, Affiliated Hospital of Jining Medical University, Jining, Shandong 273500, P.R. China.

出版信息

Int J Mol Med. 2018 Mar;41(3):1584-1594. doi: 10.3892/ijmm.2018.3370. Epub 2018 Jan 9.

Abstract

MicroRNAs (miRNAs/miRs) serve a role as important regulators in cardiac hypertrophy. The present study aimed to reveal the differential expression profile of miRNAs between young and aging spontaneously hypertensive rats (SHRs) and studied the functional annotation of predicted targets. Briefly, 3‑month‑old and 12‑month‑old SHRs (n=3/group) were subjected to echocardiography, histopathological analysis and dihydroethidium staining. Subsequently, small RNA sequencing and data processing was conducted to identify the differentially expressed miRNAs between these two groups. Eight significantly upregulated miRNAs were validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), followed by in silico target gene prediction. Functional annotation analysis of the predicted targets was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. As a result, significantly impaired left ventricular diastolic function was detected in the 12‑month‑old SHRs, alongside increased myocyte cross‑sectional area and percentage area of fibrosis, elevated reactive oxygen species production and reduced microvessel density (P<0.05). Compared with the 3‑month‑old SHRs, 21 miRNAs were significantly upregulated and five miRNAs were downregulated in 12‑month‑old rats (P<0.05). Eight upregulated, remodeling‑associated miRNAs, including rno‑miR‑132‑3p, rno‑miR‑182, rno‑miR‑208b‑3p, rno‑miR‑212‑3p, rno‑miR‑214‑3p, rno‑miR‑218a‑5p, rno‑miR‑221‑3p and rno‑miR‑222‑3p, underwent bioinformatics analysis. The target genes were significantly enriched in 688 GO terms and 39 KEGG pathways, including regulation of peptidyl‑tyrosine phosphorylation, regulation of protein serine/threonine kinase activity, adrenergic signaling in cardiomyocytes, ErbB signaling pathway, mTOR signaling pathway, FoxO signaling pathway, Ras signaling pathway, insulin secretion, adipocytokine signaling pathway, HIF‑1 signaling pathway, Rap1 signaling pathway, VEGF signaling pathway and TNF signaling pathway. Collectively, the present study identified a dysregulated miRNA profile in aging SHRs, which targeted numerous signaling pathways associated with cardiac hypertrophy, autophagy, insulin metabolism, angiogenesis and inflammatory response.

摘要

微小 RNA(miRNAs/miRs)作为心脏肥大的重要调节因子发挥作用。本研究旨在揭示年轻和衰老自发性高血压大鼠(SHR)之间 miRNA 的差异表达谱,并研究预测靶标的功能注释。简要地说,3 月龄和 12 月龄 SHR(每组 3 只)接受超声心动图、组织病理学分析和二氢乙啶染色。随后,进行小 RNA 测序和数据处理以鉴定两组之间差异表达的 miRNA。通过逆转录-定量聚合酶链反应(RT-qPCR)验证 8 个显著上调的 miRNA,随后进行靶基因预测。使用基因本体论(GO)和京都基因与基因组百科全书(KEGG)数据库对预测靶标的功能注释进行分析。结果显示,12 月龄 SHR 的左心室舒张功能显著受损,心肌横截面积和纤维化面积百分比增加,活性氧(ROS)产生增加,微血管密度降低(P<0.05)。与 3 月龄 SHR 相比,12 月龄大鼠中有 21 个 miRNA 显著上调,5 个 miRNA 下调(P<0.05)。8 个上调的、与重构相关的 miRNA,包括 rno-miR-132-3p、rno-miR-182、rno-miR-208b-3p、rno-miR-212-3p、rno-miR-214-3p、rno-miR-218a-5p、rno-miR-221-3p 和 rno-miR-222-3p,进行了生物信息学分析。靶基因显著富集于 688 个 GO 术语和 39 个 KEGG 途径,包括肽基酪氨酸磷酸化的调节、蛋白丝氨酸/苏氨酸激酶活性的调节、心肌细胞中的肾上腺素能信号传导、表皮生长因子受体(ErbB)信号通路、雷帕霉素靶蛋白(mTOR)信号通路、叉头框蛋白(FoxO)信号通路、Ras 信号通路、胰岛素分泌、脂肪细胞因子信号通路、缺氧诱导因子(HIF)-1 信号通路、Rap1 信号通路、血管内皮生长因子(VEGF)信号通路和肿瘤坏死因子(TNF)信号通路。综上所述,本研究在衰老 SHR 中鉴定到失调的 miRNA 谱,这些 miRNA 靶向与心脏肥大、自噬、胰岛素代谢、血管生成和炎症反应相关的多个信号通路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8764/5819922/a372a0eeb486/IJMM-41-03-1584-g00.jpg

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