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LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d.

ABSTRACT: Rationale: Cardiac fibrosis is associated with various cardiovascular diseases and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac diseases. However, the potential roles and underlying mechanisms of lncRNAs in cardiac fibrosis have not been explicitly delineated. Methods and Results: Using a combination of in vitro and in vivo studies, we identified a lncRNA NONMMUT022555, which is designated as a pro-fibrotic lncRNA (PFL), and revealed that PFL is up-regulated in the hearts of mice in response to myocardial infarction (MI) as well as in the fibrotic cardiac fibroblasts (CFs). We found that knockdown of PFL by adenoviruses carrying shRNA attenuated cardiac interstitial fibrosis and improved ejection fraction (EF) and fractional shortening (FS) in MI mice. Further study showed that forced expression of PFL promoted proliferation, fibroblast-myofibroblast transition and fibrogenesis in mice CFs by regulating let-7d, whereas silencing PFL mitigated TGF-?1-induced myofibroblast generation and fibrogenesis. More importantly, PFL acted as a competitive endogenous RNA (ceRNA) of let-7d, as forced expression of PFL reduced the expression and activity of let-7d. Moreover, let-7d levels were decreased in the MI mice and in fibrotic CFs. Inhibition of let-7d resulted in fibrogenesis in CFs, whereas forced expression of let-7d abated fibrogenesis through targeting platelet-activating factor receptor (Ptafr). Furthermore, overexpression of let-7d by adenoviruses carrying let-7d precursor impeded cardiac fibrosis and improved cardiac function in MI mice. Conclusion: Taken together, our study elucidated the role and mechanism of PFL in cardiac fibrosis, indicating the potential role of PFL inhibition as a novel therapy for cardiac fibrosis.

SUBMITTER: Liang H

PROVIDER: S-EPMC5817119 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d.

Liang Haihai H Pan Zhenwei Z Zhao Xiaoguang X Liu Li L Sun Jian J Su Xiaomin X Xu Chaoqian C Zhou Yuhong Y Zhao Dandan D Xu Bozhi B Li Xuelian X Yang Baofeng B Lu Yanjie Y Shan Hongli H

Theranostics 20180202 4

Rationale: Cardiac fibrosis is associated with various cardiovascular diseases and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac diseases. However, the potential roles and underlying mechanisms of lncRNAs in cardiac fibrosis have not been explicitly delineated. Methods and Results: Using a combination of in vitro and in vivo studies, we identified a ln ...[more]

PMID: 29464008

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Project description:Background: Precise classification has been reported as a central challenge in the clinical research on diagnosis and prediction of treatment efficacy in asthma. In this study, the aim was to investigate the underlying competing endogenous RNA network mechanism of asthma, especially T2 asthma, as well as to find more diagnostic biomarkers and effective therapeutic targets. Methods: Multiple sets of T2 asthma airway biopsy transcription profiles were collected, which involved long non-coding RNA (lncRNA), mRNA, and microRNA (miRNA). DIANA-LncBase, targetscan, mirwalk, and miRDB databases were employed to predict interactions between lncRNAs, miRNAs and target mRNAs. To identify mRNAs correlated with T2 asthma, differential expression and network analyses were conducted through weighted gene co-expression network analysis (WGCNA). Subsequently, the expressions of potential biomarkers were examined through qRT-PCR analysis in the T2 asthma coreinteracting cellular factor (IL-13/IL-33) induced experimental model. Lastly, the ceRNA network was confirmed by plasmid transfection and RNAi experiments in a 16HBE cell line. Results: 30 lncRNAs, 22 miRNAs and 202 mRNAs were differentially expressed in airway biopsies from T2 asthma patients. As indicated by the ROC analysis, the lncRNA, PCAT19, had high diagnostic accuracy (AUC >0.9) in distinguishing T2 asthma patients from non-T2 asthma patients and healthy controls. Furthermore, a competing ceRNA network was established, consisting of 13 lncRNAs, 12 miRNAs, as well as eight mRNAs. The reliability of this network was verified by testing several representative interactions in the network. Conclusion: To the best of our knowledge, this study has been the first to establish an lncRNA-mediated ceRNA regulatory network for studying T2 asthma. The findings of this study may elucidate the pathogenesis and help find potential therapeutic targets for T2 asthma. In T2 asthma, PCAT19-dominated ceRNA regulation networks may play a critical role, and PCAT19 may serve as a potential immune-related biomarker for asthma and other respiratory diseases correlated with eosinophilic inflammation.

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Project description:BackgroundPulpitis is a common inflammatory disease that affects dental pulp. It is important to understand the molecular signals of inflammation and repair associated with this process. Increasing evidence has revealed that long noncoding RNAs (lncRNAs), via competitively sponging microRNAs (miRNAs), can act as competing endogenous RNAs (ceRNAs) to regulate inflammation and reparative responses. The aim of this study was to elucidate the potential roles of lncRNA, miRNA and messenger RNA (mRNA) ceRNA networks in pulpitis tissues compared to normal control tissues.MethodsThe oligo and limma packages were used to identify differentially expressed lncRNAs and mRNAs (DElncRNAs and DEmRNAs, respectively) based on expression profiles in two datasets, GSE92681 and GSE77459, from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were further analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein-protein interaction (PPI) networks and modules were established to screen hub genes using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and the Molecular Complex Detection (MCODE) plugin for Cytoscape, respectively. Furthermore, an lncRNA-miRNA-mRNA-hub genes regulatory network was constructed to investigate mechanisms related to the progression and prognosis of pulpitis. Then, quantitative real-time polymerase chain reaction (qRT-PCR) was applied to verify critical lncRNAs that may significantly affect the pathogenesis in inflamed and normal human dental pulp.ResultsA total of 644 upregulated and 264 downregulated differentially expressed genes (DEGs) in pulpitis samples were identified from the GSE77459 dataset, while 8 up- and 19 downregulated probes associated with lncRNA were identified from the GSE92681 dataset. Protein-protein interaction (PPI) based on STRING analysis revealed a network of DEGs containing 4,929 edges and 623 nodes. Upon combined analysis of the constructed PPI network and the MCODE results, 10 hub genes, including IL6, IL8, PTPRC, IL1B, TLR2, ITGAM, CCL2, PIK3CG, ICAM1, and PIK3CD, were detected in the network. Next, a ceRNA regulatory relationship consisting of one lncRNA (PVT1), one miRNA (hsa-miR-455-5p) and two mRNAs (SOCS3 and PLXNC1) was established. Then, we constructed the network in which the regulatory relationship between ceRNA and hub genes was summarized. Finally, our qRT-PCR results confirmed significantly higher levels of PVT1 transcript in inflamed pulp than in normal pulp tissues (p = 0.03).ConclusionOur study identified a novel lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of pulpitis.

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LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d.

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LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d.

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