Integrated Bioinformatic Analysis Reveals TXNRD1 as a Novel Biomarker and Potential Therapeutic Target in Idiopathic Pulmonary Arterial Hypertension

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening cardiopulmonary disease lacking specific diagnostic markers and targeted therapy, and its mechanism of development remains to be elucidated. The present study aimed to explore novel diagnostic biomarkers and therapeutic targets in IPAH by integrated bioinformatics analysis. Four eligible datasets (GSE117261, GSE15197, GSE53408, GSE48149) was firstly downloaded from GEO database and subsequently integrated by Robust rank aggregation (RRA) method to screen robust differentially expressed genes (DEGs). Then functional annotation of robust DEGs was performed by GO and KEGG enrichment analysis. The protein-protein interaction (PPI) network was constructed followed by using MCODE and CytoHubba plug-in to identify hub genes. Finally, 10 hub genes were screened including ENO1, TALDO1, TXNRD1, SHMT2, IDH1, TKT, PGD, CXCL10, CXCL9, and CCL5. The GSE113439 dataset was used as a validation cohort to appraise these hub genes and TXNRD1 was selected for verification at the protein level. The experiment results confirmed that serum TXNRD1 concentration was lower in IPAH patients and the level of TXNRD1 had great predictive efficiency (AUC:0.795) as well as presents negative correlation with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). Consistently, the expression of TXNRD1 was proved to be inhibited in animal and cellular model of PAH. In addition, GSEA analysis was performed to explore the functions of TXNRD1 and the results revealed that TXNRD1 was closely correlated with mTOR signaling pathway, MYC targets, and unfolded protein response. Finally, knockdown of TXNRD1 was shown to exacerbate proliferative disorder, migration and apoptosis resistance in PASMCs. In conclusion, our study demonstrates that TXNRD1 is a promising candidate biomarker for diagnosis of IPAH and plays an important role in PAH pathogenesis, although further research is necessary.

Bioinformatics analysis of the immune cell infiltration characteristics and correlation with crucial diagnostic markers in pulmonary arterial hypertension

“…TXNRD1, a member of the thioredoxin (Trx) system that catalyzes Trx1 reduction, plays a vital role in redox homeostasis [ 32 ]. In our study, it was shown that TXNRD1 mRNA was significantly decreased in human PAH lung samples by bioinformatics, which is consistent with previous reports [ 6 , 33 ]. TXNRD1 was also downregulated in the serum of PAH patients and lungs of MCT-induced PAH rats [ 6 , 34 ].…”

“…Immunity and inflammation are progressively recognized properties of PAH. A large amount of evidence has demonstrated that inflammation and immunity play vital roles in the initiation and maintenance of pulmonary vascular remodeling in PAH [ 6 – 9 ]. An accumulation of macrophages, B and T cells, mast cells, and dendritic cells (DCs) was observed in the lungs or around the pulmonary vessels of PAH [ 9 – 13 ].…”

Identification of immune-related hub genes and analysis of infiltrated immune cells of idiopathic pulmonary artery hypertension

“…Cunningham et al reported that treatment with CXCL10 could trigger the apoptosis of PAEC, and inhibition of CXCL10 in rat could significantly reduce the severity of pulmonary hypertension (44). There are other bioinformatics researches identified CXCL10 as hub gene of IPAH (45,46). VIPR1 (vasoactive intestinal peptide receptor 1) plays an important role in smooth muscle relaxation and acts as an antiinflammatory cytokine (47), which is significantly downregulated in the IPAH group of lung dataset and PBMCs dataset.…”

Expression profiles of circRNAs and identification of hsa_circ_0007608 and hsa_circ_0064656 as potential biomarkers for COPD-PH patients

“…Bioinformatics tools has been widely applied in oncology to identify genetic changes and new potential biomarkers associated with various diseases [14][15][16] . Likewise, researchers have tried to apply bioinformtics analysis in the study of PH to to elucidate the potential functions of circRNAs related to PH, mostly based on databases and animal experiments [17][18][19][20][21][22][23][24][25][26] . However, few studies have utilized clinical samples with definite diagnosis of PH, and researches for PH in COPD are even fewer.…”