Molecular Characterization and Elucidation of Pathways to Identify Novel Therapeutic Targets in Pulmonary Arterial Hypertension.

Xiaoting Yao,Xi Chen,Hao Feng,Fengqiang Chen,Tianxing Wang,Chenxin Gu,Huiying Zhao,Dekun Chen,Wentao Ma,Tian Jing

doi:10.3389/fphys.2021.694702

Xiaoting Yao, Xi Chen + Show 8 more

Open Access

https://doi.org/10.3389/fphys.2021.694702

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Abstract

Background: Pulmonary arterial hypertension (PAH) is a life-threatening chronic cardiopulmonary disease. However, there are limited studies reflecting the available biomarkers from separate gene expression profiles in PAH. This study explored two microarray datasets by an integrative analysis to estimate the molecular signatures in PAH.Methods: Two microarray datasets (GSE53408 and GSE113439) were exploited to compare lung tissue transcriptomes of patients and controls with PAH and to estimate differentially expressed genes (DEGs). According to common DEGs of datasets, gene and protein overrepresentation analyses, protein–protein interactions (PPIs), DEG–transcription factor (TF) interactions, DEG–microRNA (miRNA) interactions, drug–target protein interactions, and protein subcellular localizations were conducted in this study.Results: We obtained 38 common DEGs for these two datasets. Integration of the genome transcriptome datasets with biomolecular interactions revealed hub genes (HSP90AA1, ANGPT2, HSPD1, HSPH1, TTN, SPP1, SMC4, EEA1, and DKC1), TFs (FOXC1, FOXL1, GATA2, YY1, and SRF), and miRNAs (hsa-mir-17-5p, hsa-mir-26b-5p, hsa-mir-122-5p, hsa-mir-20a-5p, and hsa-mir-106b-5p). Protein–drug interactions indicated that two compounds, namely, nedocromil and SNX-5422, affect the identification of PAH candidate biomolecules. Moreover, the molecular signatures were mostly localized in the extracellular and nuclear areas.Conclusions: In conclusion, several lung tissue-derived molecular signatures, highlighted in this study, might serve as novel evidence for elucidating the essential mechanisms of PAH. The potential drugs associated with these molecules could thus contribute to the development of diagnostic and therapeutic strategies to ameliorate PAH.

Highlights

Pulmonary arterial hypertension (PAH) is a rare vascular disease with an annual incidence of two cases per million (Peacock et al, 2007)
PAH is defined by a mean pulmonary arterial pressure > 20 mmHg at rest, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) ≥ 3.0 Wood units (Gouyou et al, 2021)
The datasets were obtained from two separate studies on human lung tissues that were compared across normal individuals and patients with PAH on Affymetrix microarrays, which have been deposited in the NCBI-gene expression omnibus (GEO) database under the accession numbers GSE53408 and GSE113439

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a rare vascular disease with an annual incidence of two cases per million (Peacock et al, 2007). PAH is characterized by high pulmonary arterial pressure, resulting in right ventricular failure and even death (Boucly et al, 2017; Tang et al, 2018). Current diagnosis and therapy strategies have effectively ameliorated the abnormal hemodynamics and severe pulmonary vascular remodeling of PAH, and efficaciously alleviated the clinical symptoms in patients with PAH, there are still a number of patients suffering from persistent symptoms and even right heart failure (Van De Veerdonk et al, 2011, 2015). Pulmonary arterial hypertension (PAH) is a life-threatening chronic cardiopulmonary disease.

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