Lin Wenchao, Tang Yiyang, Zhang Mengqiu, Liang Benhui, Wang Meijuan, Zha Lihuang, Yu Zaixin
Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China.
Front Med (Lausanne). 2022 May 12;9:894584. doi: 10.3389/fmed.2022.894584. eCollection 2022.
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和靶向治疗方法，其发病机制仍有待阐明。本研究旨在通过综合生物信息学分析探索IPAH的新型诊断生物标志物和治疗靶点。首先从GEO数据库下载了四个符合条件的数据集（GSE117261、GSE15197、GSE53408、GSE48149），随后通过稳健秩聚合（RRA）方法进行整合，以筛选出稳健的差异表达基因（DEG）。然后通过GO和KEGG富集分析对稳健的DEG进行功能注释。构建蛋白质-蛋白质相互作用（PPI）网络，随后使用MCODE和CytoHubba插件来识别枢纽基因。最后，筛选出10个枢纽基因，包括ENO1、TALDO1、TXNRD1、SHMT2、IDH1、TKT、PGD、CXCL10、CXCL9和CCL5。使用GSE113439数据集作为验证队列来评估这些枢纽基因，并选择TXNRD1在蛋白质水平进行验证。实验结果证实，IPAH患者血清TXNRD1浓度较低，TXNRD1水平具有较高的预测效率（AUC：0.795），并且与平均肺动脉压（mPAP）和肺血管阻力（PVR）呈负相关。同样，在PAH动物和细胞模型中，TXNRD1的表达被证明受到抑制。此外，进行了基因集富集分析（GSEA）以探索TXNRD1的功能，结果显示TXNRD1与mTOR信号通路、MYC靶点和未折叠蛋白反应密切相关。最后，敲低TXNRD1可加剧肺动脉平滑肌细胞（PASMC）的增殖紊乱、迁移和抗凋亡能力。总之，我们的研究表明，TXNRD1是IPAH诊断的一个有前景的候选生物标志物，并且在PAH发病机制中起重要作用，尽管还需要进一步研究。
