Abstract
Objective: Increasing evidence has uncovered the roles of lncRNA-miRNA-mRNA regulatory networks in cardiovascular diseases. However, the crosstalk between ceRNA networks and development of heart failure (HF) remains unclear. This study was to investigate the role of lncRNA-mediated ceRNA networks in the pathophysiological process of HF and its potential regulatory functions on programmed cell death.Methods: We firstly screened the GSE77399, GSE52601 and GSE57338 datasets in the NCBI GEO database for screening differentially expressed lncRNAs, miRNAs and mRNAs. lncRNA-miRNA-mRNA regulatory networks based on the ceRNA theory were subsequently constructed. GO and KEGG enrichment analysis was conducted to predict potential biological functions of mRNAs in ceRNA networks. Differentially expressed mRNAs were then interacted with programmed cell death related genes. lncRNA-mediated ceRNA regulatory pathways on programmed cell death were validated with qRT-PCR testing.Results: Based on our bioinformatic analysis, two lncRNAs, eight miRNAs and 65 mRNAs were extracted to construct two lncRNAs-mediated ceRNA networks in HF. Biological processes and pathways were enriched in extracellular matrix. Seven lncRNA-mediated ceRNA regulatory pathways on programmed cell death, GAS5/miR-345-5p/ADAMTS4, GAS5/miR-18b-5p/AQP3, GAS5/miR-18b-5p/SHISA3, GAS5/miR-18b-5p/C1orf105, GAS5/miR-18b-5p/PLIN2, GAS5/miR-185-5p/LPCAT3, and GAS5/miR-29b-3p/STAT3, were finally validated.Conclusions: Two novel ceRNA regulatory networks in HF were discovered based on our bioinformatic analysis. Based on the interaction and validation analysis, seven lncRNA GAS5-mediated ceRNA regulatory pathways were hypothesized to impact programmed cell death including seven for apoptosis, three for ferroptosis, and one for pyroptosis. Upon which, we provided novel insights and potential research plots for bridging ceRNA regulatory networks and programmed cell death in HF.
Highlights
Heart Failure (HF) is the terminal stage of various cardiovascular diseases
To identify potential differential long non-coding RNAs (lncRNAs), miRNAs and mRNAs in HF, a comparative analysis for expression profiles of lncRNAs, miRNAs and mRNAs between patients with HF and healthy controls using GEO dataset was performed with P < 0.05 and |log fold change [FC]|>0.5 as threshold
Based on the interaction elements, five miRNA-lncRNA pairs and 51 miRNA-mRNA pairs were identified in the upregulated miRNA competitive endogenous RNA (ceRNA) network, and 3 miRNA-lncRNA pairs and 31 miRNAmRNA pairs in the downregulated miRNA ceRNA network
Summary
Heart Failure (HF) is the terminal stage of various cardiovascular diseases. Advanced interventions, such as pharmacological treatment, cardiac resynchronous treatment, cardiac transplantation, mainly focus on HF related symptom control [1]. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are a group of RNAs that play critical roles in cellular and molecular physiology and pathology including epigenetic, transcriptional regulation, and post-transcriptional regulation [3]. Among these ncRNAs, increasing evidence indicates that lncRNA was widely involved in the pathological process of cardiac development, atherosclerosis, myocardial infarction, hypertension and aneurysm [4,5,6]. Evidence suggests that lncRNAs may not perform modulatory functions independently while create dynamic regulatory crosstalk networks by interacting with other ncRNAs through competitively binding to certain ncRNAs, which was previously termed as the competitive endogenous RNA (ceRNA) network theory [11]
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