Data_Sheet_7_Integrated Bioinformatic Analysis Reveals TXNRD1 as a Novel Biomarker and Potential Therapeutic Target in Idiopathic Pulmonary Arterial Hypertension.CSV

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.

特发性肺动脉高压（IPAH）是一种危及生命的心肺疾病，缺乏特异性诊断标志物与靶向治疗手段，其发病机制仍有待阐明。本研究旨在通过整合生物信息学分析，探索特发性肺动脉高压（IPAH）中新的诊断生物标志物与治疗靶点。研究人员首先从GEO数据库（Gene Expression Omnibus）下载了4个符合入组标准的数据集（GSE117261、GSE15197、GSE53408、GSE48149），随后通过稳健秩聚合（RRA）方法对其进行整合，以筛选稳健差异表达基因（DEGs）。随后通过基因本体（GO, Gene Ontology）富集分析与京都基因与基因组百科全书（KEGG, Kyoto Encyclopedia of Genes and Genomes）富集分析，对稳健差异表达基因进行功能注释。构建蛋白质相互作用（PPI）网络后，借助MCODE与CytoHubba插件筛选核心基因。最终筛选得到10个核心基因，分别为ENO1、TALDO1、TXNRD1、SHMT2、IDH1、TKT、PGD、CXCL10、CXCL9及CCL5。以GSE113439数据集作为验证队列对上述核心基因进行评估，并选取TXNRD1进行蛋白水平验证。实验结果证实，特发性肺动脉高压患者血清TXNRD1浓度更低，且TXNRD1水平具有良好的预测效能（受试者工作特征曲线下面积AUC：0.795），同时与平均肺动脉压（mPAP）、肺血管阻力（PVR）呈负相关。与之相符的是，在肺动脉高压（PAH, Pulmonary Arterial Hypertension）动物模型与细胞模型中，TXNRD1的表达均被抑制。此外，通过基因集富集分析（GSEA, Gene Set Enrichment Analysis）探索TXNRD1的功能，结果显示TXNRD1与mTOR信号通路、MYC靶点及未折叠蛋白反应密切相关。最终实验证实，敲低TXNRD1会加剧肺动脉平滑肌细胞（PASMCs, Pulmonary Artery Smooth Muscle Cells）的增殖异常、迁移增强及凋亡抵抗现象。综上，本研究表明TXNRD1是一种颇具潜力的特发性肺动脉高压诊断候选生物标志物，且在肺动脉高压的发病机制中发挥重要作用，不过仍需开展进一步的相关研究。