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RNA-Binding Proteins in Pulmonary Hypertension.

ABSTRACT: Pulmonary hypertension (PH) is a life-threatening disease characterized by significant vascular remodeling and aberrant expression of genes involved in inflammation, apoptosis resistance, proliferation, and metabolism. Effective therapeutic strategies are limited, as mechanisms underlying PH pathophysiology, especially abnormal expression of genes, remain unclear. Most PH studies on gene expression have focused on gene transcription. However, post-transcriptional alterations have been shown to play a critical role in inflammation and metabolic changes in diseases such as cancer and systemic cardiovascular diseases. In these diseases, RNA-binding proteins (RBPs) have been recognized as important regulators of aberrant gene expression via post-transcriptional regulation; however, their role in PH is less clear. Identifying RBPs in PH is of great importance to better understand PH pathophysiology and to identify new targets for PH treatment. In this manuscript, we review the current knowledge on the role of dysregulated RBPs in abnormal mRNA gene expression as well as aberrant non-coding RNA processing and expression (e.g., miRNAs) in PH.

SUBMITTER: Zhang H

PROVIDER: S-EPMC7312837 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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RNA-Binding Proteins in Pulmonary Hypertension.

Zhang Hui H Brown R Dale RD Stenmark Kurt R KR Hu Cheng-Jun CJ

International journal of molecular sciences 20200526 11

Pulmonary hypertension (PH) is a life-threatening disease characterized by significant vascular remodeling and aberrant expression of genes involved in inflammation, apoptosis resistance, proliferation, and metabolism. Effective therapeutic strategies are limited, as mechanisms underlying PH pathophysiology, especially abnormal expression of genes, remain unclear. Most PH studies on gene expression have focused on gene transcription. However, post-transcriptional alterations have been shown to p ...[more]

PMID: 32466553

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Project description:BACKGROUND:Sarcoidosis is characterised by up-regulation of cytokines and chemokine ligands/receptors and proteolytic enzymes. This pro-inflammatory profile is regulated post-transcriptionally by RNA-binding proteins (RBPs). We investigated in vivo expression of six RBPs (AUF1, HuR, NCL, TIA, TIAR, PCBP2) and two inhibitors of proteolytic enzymes (RECK, PTEN) in pulmonary sarcoidosis and compared it to the expression in four control groups of healthy individuals and patients with other respiratory diseases: chronic obstructive pulmonary disease (COPD), asthma and idiopathic interstitial pneumonias (IIPs). METHODS:RT-PCR was used to quantify the mRNAs in bronchoalveolar (BA) cells obtained from 50 sarcoidosis patients, 23 healthy controls, 30 COPD, 19 asthmatic and 19 IIPs patients. Flow cytometry was used to assess intracellular protein expression of AUF1 and HuR in peripheral blood T lymphocytes (PBTLs) obtained from 9 sarcoidosis patients and 6 healthy controls. RESULTS:Taking the stringent conditions for multiple comparisons into consideration, we consistently observed in the primary analysis including all patients regardless of smoking status as well as in the subsequent sub-analysis limited for never smokers that the BA mRNA expression of AUF1 (p<0.001), TIA (p<0.001), NCL (p<0.01) and RECK (p<0.05) was decreased in sarcoidosis compared to healthy controls. TIA mRNA was also decreased in sarcoidosis compared to both obstructive pulmonary diseases (COPD and asthma; p<0.001) but not compared to IIPs. There were several positive correlations between RECK mRNA and RBP mRNAs in BA cells. Also sarcoidosis CD3+, CD4+ and CD8+ PBTLs displayed lower mean fluorescence intensity of AUF1 (p?0.02) and HuR (p?0.03) proteins than control healthy PBTLs. CONCLUSION:mRNA expressions of three RBPs (AUF1, TIA and NCL) and their potential target mRNA encoding RECK in BA cells and additionally protein expression of AUF1 and HuR in PBTLs were down-regulated in our sarcoidosis patients compared to healthy individuals. Its significance, e.g. for stability of mRNAs encoding pro-inflammatory factors, should be further explored in sarcoidosis.

Project description:BackgroundRNA-binding proteins are master orchestrators of gene expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs. Thus, characterizing RNA-binding proteins targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RNA-binding protein targets, limiting our understanding of their function. In cancer, the RNA-binding protein HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1; A2B1) promotes the pro-proliferative/anti-apoptotic phenotype. The same phenotype in pulmonary arterial smooth muscle cells (PASMCs) is responsible for the development of pulmonary arterial hypertension (PAH). However, A2B1 function has never been investigated in PAH.MethodThrough the integration of computational and experimental biology, the authors investigated the role of A2B1 in human PAH-PASMC. Bioinformatics and RNA sequencing allowed them to investigate the transcriptome-wide function of A2B1, and RNA immunoprecipitation and A2B1 silencing experiments allowed them to decipher the intricate molecular mechanism at play. In addition, they performed a preclinical trial in the monocrotaline-induced pulmonary hypertension rat model to investigate the relevance of A2B1 inhibition in mitigating pulmonary hypertension severity.ResultsThey found that A2B1 expression and its nuclear localization are increased in human PAH-PASMC. Using bioinformatics, they identified 3 known motifs of A2B1 and all mRNAs carrying them. In PAH-PASMC, they demonstrated the complementary nonredundant function of A2B1 motifs because all motifs are implicated in different aspects of the cell cycle. In addition, they showed that in PAH-PASMC, A2B1 promotes the expression of its targets. A2B1 silencing in PAH-PASMC led to a decrease of all tested mRNAs carrying an A2B1 motif and a concomitant decrease in proliferation and resistance to apoptosis. Last, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats.ConclusionsThrough the integration of computational and experimental biology, the study revealed the role of A2B1 as a master orchestrator of the PAH-PASMC phenotype and its relevance as a therapeutic target in PAH.

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RNA-Binding Proteins in Pulmonary Hypertension.

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RNA-Binding Proteins in Pulmonary Hypertension.

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