Identification and experimental verification of senescence-related gene signatures and molecular subtypes in idiopathic pulmonary arterial hypertension

Abstract

Abstract Evidences illustrate that cell senescence contributes to the development of pulmonary arterial hypertension. However, the molecular mechanisms remain unclear. Since there may be different senescence subtypes between PAH patients, consistent senescence-related genes (SRGs) were utilized for consistent clustering by unsupervised clustering methods. Senescence is inextricably linked to the immune system, and the immune cells in each cluster were estimated by ssGSEA. To further screen out more important SRGs, machine learning algorithms were used for identification and their diagnostic value was assessed by ROC curves. The expression of hub genes were verified in vivo and in vitro. Transcriptome analysis was used to assess the effects of silence of hub gene on different pathways. Three senescence molecular subtypes were identified by consensus clustering. Compared with cluster A and B, most immune cells and checkpoint genes were higher in cluster C. Thus, we identified senescence cluster C as the immune subtype. The ROC curves of IGF1, HOXB7, and YWHAZ were remarkable in both datasets. The expression of these genes was increased in vitro. Western blot and immunohistochemical analyses revealed that YWHAZ expression was also increased. Our transcriptome analysis showed autophagy-related genes were significantly elevated after silence of YWHAZ. Our research provided several prospective SRGs and molecular subtypes. Silence of YWHAZ may contribute to the clearance of senescent endothelial cells by activating autophagy.

Keywords

• Senescence-related genes
• Pulmonary arterial hypertension
• Machine learning
• Molecular subtypes
• Immune infiltration
• Transcriptome analysis