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Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro
Published on: May 10, 2021
Integrated Analysis of LncRNA-Mediated ceRNA Network in Calcific Aortic Valve Disease
1State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, China & Department of Cardiovascular Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100006, China.
Background:
The high morbidity and mortality of calcific aortic valve disease (CAVD) represents an unmet clinical need to investigate the molecular mechanisms involved. Evidence suggests that long non-coding RNAs (lncRNAs) can act as competitive endogenous RNAs (ceRNAs) by binding to microRNAs and regulating target genes in cardiovascular diseases. Nevertheless, the role of lncRNAs related ceRNA regulation in CAVD remains unclear.
Methods:
RNAseq data of human diseased aortic valves were downloaded from GEO data sets (GSE153555, GSE199718), and differentially expressed lncRNAs (DElncRNAs), mRNAs (DEmRNAs) between CAVD and non-calcific aortic valve tissues with limma R package. Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Set Enrichment analysis (GSEA) were performed with clusterProfiler and gesaplot2 R package. The pivotal microRNAs were predicted by three databases intersection including TargetScan, MiRwalk, miRDB according to the genes related to the crucial pathways. ENCORI was used to predict targeted lncRNAs of hub microRNAs. We constructed lncRNA-miRNA-mRNA ceRNA network with Cytoscape software. The lncRNAs in ceRNA network were verified by RT-qPCR in human 30 calcific and 20 noncalcified aortic valve tissues.
Results:
In total, 1739 DEmRNAs and 266 DElncRNAs were identified in CAVD. GO, KEGG pathway, GSEA annotations suggested that most of these genes are enriched in extracellular matrix (ECM)-reporter interaction pathways. The ceRNA networks associated with ECM-reporter interaction are constructed and related lncRNAs including H19, SNHG3 and ZNF436-AS1 were significant upregulated in human calcific aortic valve tissues, which might be potential therapeutic targets for CAVD.
Conclusions:
In this study, we proposed a novel lncRNA-miRNA-mRNA ceRNA network related to ECM-reporter interaction pathways, which potentially regulates CAVD progression.
Insights
This study uncovers a novel long non-coding RNA (lncRNA)-microRNA-messenger RNA (mRNA) regulatory network in calcific aortic valve disease (CAVD). Key lncRNAs like H19 may offer new therapeutic targets for this condition.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- RNA Biology
Background:
- Calcific aortic valve disease (CAVD) presents significant morbidity and mortality, necessitating research into its underlying molecular mechanisms.
- Long non-coding RNAs (lncRNAs) are implicated as competitive endogenous RNAs (ceRNAs) in cardiovascular diseases, but their specific role in CAVD remains largely unknown.
Purpose of the Study:
- To investigate the role of lncRNA-mediated ceRNA networks in the pathogenesis of CAVD.
- To identify potential molecular targets for therapeutic intervention in CAVD.
Main Methods:
- Differential expression analysis of lncRNAs and mRNAs in CAVD tissues using RNA sequencing data.
- Gene Ontology, KEGG pathway, and Gene Set Enrichment analyses to identify enriched biological pathways.
- Prediction of microRNA targets and construction of a lncRNA-miRNA-mRNA ceRNA network using bioinformatics tools.
- Validation of key lncRNAs via RT-qPCR in human aortic valve tissue samples.
Main Results:
- Identification of 1739 differentially expressed mRNAs and 266 differentially expressed lncRNAs in CAVD.
- Enrichment analysis revealed that these genes are predominantly involved in extracellular matrix (ECM)-reporter interaction pathways.
- Construction of ceRNA networks associated with ECM pathways, highlighting upregulated lncRNAs (H19, SNHG3, ZNF436-AS1) in CAVD tissues.
Conclusions:
- A novel lncRNA-miRNA-mRNA ceRNA network associated with ECM-reporter interaction pathways has been proposed.
- This network potentially plays a crucial role in regulating the progression of calcific aortic valve disease.
- Upregulated lncRNAs such as H19, SNHG3, and ZNF436-AS1 represent potential therapeutic targets for CAVD.
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