Wang Wei, Jiang Zhenhong, Zhang Dandan, Fu Linghua, Wan Rong, Hong Kui
Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Front Cell Dev Biol. 2021 Jul 15;9:672159. doi: 10.3389/fcell.2021.672159. eCollection 2021.
Pulmonary arterial hypertension (PAH) is a severe cardiovascular disorder with high mortality. Multiple clinical diseases can induce PAH, but the underlying molecular mechanisms shared in PAHs associated with different diseases remain unclear. The aim of this study is to explore the key candidate genes and pathways in PAH associated with congenital heart disease (CHD-PAH), PAH associated with connective tissue disease (CTD-PAH), and idiopathic PAH (IPAH). We performed differential expression analysis based on a public microarray dataset GSE113439 and identified 1,442 differentially expressed genes, of which 80.3% were upregulated. Subsequently, both pathway enrichment analysis and protein-protein interaction network analysis revealed that the "Cell cycle" and "DNA damage" processes were significantly enriched in PAH. The expression of seven upregulated candidate genes (, , , , and -) and three downregulated candidate genes (, , and ) were validated by qRT-PCR. Furthermore, cell cycle-related genes and were identified in pulmonary arterial endothelial cells (PAECs) The result revealed an increased expression of in PAECs after hypoxic treatment. Silencing could inhibit overproliferation and migration of PAECs in hypoxia. Taken together, according to bioinformatic analyses, our work revealed that "Cell cycle" and "DNA damage" process-related genes and pathways were significantly dysregulated expressed in PAHs associated with three different diseases. This commonality in molecular discovery might broaden the genetic perspective and understanding of PAH. Besides, silencing showed a protective effect in PAECs in hypoxia. The results may provide new treatment targets in multiple diseases induced by PAH.
肺动脉高压（PAH）是一种死亡率高的严重心血管疾病。多种临床疾病可诱发PAH，但不同疾病相关PAH中共同的潜在分子机制仍不清楚。本研究的目的是探索与先天性心脏病相关的PAH（CHD-PAH）、与结缔组织病相关的PAH（CTD-PAH）和特发性PAH（IPAH）中的关键候选基因和通路。我们基于公开的微阵列数据集GSE113439进行差异表达分析，鉴定出1442个差异表达基因，其中80.3%上调。随后，通路富集分析和蛋白质-蛋白质相互作用网络分析均显示，“细胞周期”和“DNA损伤”过程在PAH中显著富集。通过qRT-PCR验证了7个上调候选基因（、、、、和-）和3个下调候选基因（、和）的表达。此外，在肺动脉内皮细胞（PAECs）中鉴定出细胞周期相关基因和 结果显示缺氧处理后PAECs中表达增加。沉默可抑制PAECs在缺氧状态下的过度增殖和迁移。综上所述，根据生物信息学分析，我们的研究表明，“细胞周期”和“DNA损伤”过程相关的基因和通路在与三种不同疾病相关的PAH中显著失调表达。这种分子发现中的共性可能拓宽对PAH的遗传学视角和理解。此外，沉默在缺氧的PAECs中显示出保护作用。这些结果可能为PAH诱发的多种疾病提供新的治疗靶点。
