Du Yan, Zhang Jingqiu, Guo Kai, Yin Yongxiang
Department of Pathology, Wuxi Maternity and Child Healthcare Hospital, Affiliated Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China.
Department of Pathology, Suzhou Science and Technology Town Hospital, Suzhou, China.
Front Genet. 2024 Mar 22;15:1328234. doi: 10.3389/fgene.2024.1328234. eCollection 2024.
Idiopathic pulmonary arterial hypertension (IPAH) is a rare and severe cardiopulmonary disease with a challenging prognosis, and its underlying pathogenesis remains elusive. A comprehensive understanding of IPAH is crucial to unveil potential diagnostic markers and therapeutic targets. In this study, we investigated cellular heterogeneity and molecular pathology in IPAH using single-cell RNA sequencing (scRNA-seq) analysis. Our scRNA-seq results revealed significant alterations in three crucial signaling pathways in IPAH: the hypoxia pathway, TGF β pathway, and ROS pathway, primarily attributed to changes in gene expression within arterial endothelial cells. Moreover, through bulk RNA sequencing analysis, we identified differentially expressed genes (DEGs) enriched in GO and KEGG pathways, implicated in regulating cell adhesion and oxidative phosphorylation in IPAH lungs. Similarly, DEGs-enriched pathways in IPAH arterial endothelial cells were also identified. By integrating DEGs from three IPAH datasets and applying protein-protein interaction (PPI) analysis, we identified 12 candidate biomarkers. Subsequent validation in two additional PAH datasets led us to highlight five potential biomarkers (CTNNB1, MAPK3, ITGB1, HSP90AA1, and DDX5) with promising diagnostic significance for IPAH. Furthermore, real-time quantitative polymerase chain reaction (RT-qPCR) confirmed significant differences in the expression of these five genes in pulmonary arterial endothelial cells from PAH mice. In conclusion, our findings shed light on the pivotal role of arterial endothelial cells in the development of IPAH. Furthermore, the integration of single-cell and bulk RNA sequencing datasets allowed us to pinpoint novel candidate biomarkers for the diagnosis of IPAH. This work opens up new avenues for research and potential therapeutic interventions in IPAH management.
特发性肺动脉高压（IPAH）是一种罕见且严重的心肺疾病，预后具有挑战性，其潜在发病机制仍不清楚。全面了解IPAH对于揭示潜在的诊断标志物和治疗靶点至关重要。在本研究中，我们使用单细胞RNA测序（scRNA-seq）分析研究了IPAH中的细胞异质性和分子病理学。我们的scRNA-seq结果显示，IPAH中三个关键信号通路存在显著改变：缺氧通路、TGFβ通路和ROS通路，主要归因于动脉内皮细胞内基因表达的变化。此外，通过批量RNA测序分析，我们鉴定了在GO和KEGG通路中富集的差异表达基因（DEG），这些通路与IPAH肺中调节细胞粘附和氧化磷酸化有关。同样，也鉴定了IPAH动脉内皮细胞中富集DEG的通路。通过整合来自三个IPAH数据集的DEG并应用蛋白质-蛋白质相互作用（PPI）分析，我们鉴定了12个候选生物标志物。随后在另外两个PAH数据集中进行验证，使我们突出了五个潜在生物标志物（CTNNB1、MAPK3、ITGB1、HSP90AA1和DDX5），它们对IPAH具有有前景的诊断意义。此外，实时定量聚合酶链反应（RT-qPCR）证实了这五个基因在PAH小鼠肺动脉内皮细胞中的表达存在显著差异。总之，我们的研究结果揭示了动脉内皮细胞在IPAH发展中的关键作用。此外，单细胞和批量RNA测序数据集整合使我们能够确定用于诊断IPAH的新型候选生物标志物。这项工作为IPAH管理的研究和潜在治疗干预开辟了新途径。
