Profiling and Molecular Mechanism Analysis of Long Non-Coding RNAs and mRNAs in Pulmonary Arterial Hypertension Rat Models.

Shiqiang Hou,Mingfei Li,Dandan Chen,Wenzhi Pan,Xiaochun Zhang,Daxin Zhou,Yuan Zhang,Lihua Guan,Jie Liu,Junbo Ge,Shasha Chen

doi:10.3389/fphar.2021.709816

Abstract

Pulmonary arterial hypertension (PAH) is an immune-mediated disease with poor prognosis and associated with various inflammatory immune diseases. In fact, its pathogenesis is far from clear. Although long non-coding RNAs (lncRNAs) have been implicated in PAH, the molecular mechanisms remain largely unknown. For the first time, in lungs of monocrotaline-induced PAH rat models, we simultaneously detected the expression profiles of lncRNAs and mRNAs by high-throughput sequencing, and explored their roles with bioinformatics analysis and cell assay to discover more potential pathogenesis about PAH. Our data identified that a total of 559 lncRNAs and 691 mRNAs were differentially expressed in lungs during the pathogenesis of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that these dysregulated lncRNAs and mRNAs participated in important biological processes and pathways of PAH, among which inflammatory and immune responses represented the chief enriched pathway. The lncRNA-mRNA co-expression network was developed to uncover the hidden interactions between lncRNAs and mRNAs. Further, the expression levels of lncRNAs (NONRATT018084.2, NONRATT009275.2, NONRATT007865.2, and NONRATT026300.2) and mRNAs (LGALS3, PDGFC, SERPINA1, and NFIL3) were confirmed using quantitative real-time PCR. In the end, lncRNA NONRATT009275.2 could facilitate macrophage polarization to M2 type and be involved in inflammatory immune response. In conclusion, this study provided candidate drug targets and potential roles on lncRNAs in the pathogenesis of PAH, and several key regulatory genes were identified, which laid the initial foundation for further mechanism study in PAH.

Highlights

Pulmonary arterial hypertension (PAH) is an immune-mediated progressive disease characterized by increases in pulmonary vascular resistance and pulmonary artery pressure that lead to right ventricular failure and death (Humbert et al, 2004)
A recent microarray analysis, in pulmonary arteries (PAs) of PAH rats induced by MCT, indicated that a total of 24 long non-coding RNAs (lncRNAs) and 82 mRNAs were aberrantly expressed (Sun et al, 2019)
In PAH rats with right ventricle (RV) failure induced by acute inflammation, 169 lncRNAs and 898 mRNAs were found to be aberrantly expressed in RV myocardium (Cao et al, 2018)

Summary

Introduction

Pulmonary arterial hypertension (PAH) is an immune-mediated progressive disease characterized by increases in pulmonary vascular resistance and pulmonary artery pressure that lead to right ventricular failure and death (Humbert et al, 2004). It is a common complication of many inflammatory immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis (Qu et al, 2021; Vonk et al, 2021). Current drug treatments are mainly based on three critical signaling pathways containing endothelin, prostacyclin, and nitric oxide They have not resulted in an effective strategy which could reverse pulmonary vascular remodeling (PVR) and prevent deterioration and the need for a lung transplant (Galiè et al, 2016). It is urgent to identify new potential therapeutic targets for PAH

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Conclusion