Identification of neutrophil extracellular traps-related genes as feature genes and potential therapeutic targets in pulmonary hypertension

Background: Neutrophil extracellular traps (NETs) might be promising targets for the evaluation and treatment of pulmonary hypertension. However, no study has systematically screened NETs as feature genes and therapeutic targets in pulmonary hypertension. The present study aims precisely to address this issue. Methods: GSE15197, GSE48149 and GSE53408 were used as the training group, whereas GSE113439 was used as the validation group for comprehensive bioinformatics analyses, and the screened feature genes were further confirmed using immunoblotting with animal lung tissues. Results: First, 12 differentially expressed NETs-related genes were significantly upregulated in pulmonary hypertension patients compared with healthy controls. Second, immune infiltration analysis revealed that immature B cells, immature dendritic cells, T helper cells and memory CD8+ T cells were increased in pulmonary hypertension patients. Third, three machine learning models identified five feature genes for pulmonary hypertension, including IQGAP2, HSP90AA1, HK2, MYO5A and NCL, which were further confirmed through animal experiments. In addition, clustering analysis revealed two distinct subtypes of pulmonary hypertension with different immune microenvironment profiles. Finally, hypothesis-generating computational screen of drug-gene interactions yielded potential inhibitors against the five feature genes. Conclusions: Five NETs-related genes, namely IQGAP2, HSP90AA1, HK2, MYO5A and NCL, were identified as feature genes for pulmonary hypertension. The immune microenvironment played an important role in the pathogenesis of pulmonary hypertension, and patients in cluster C1 were considered the main disease subtype. In addition, potential inhibitors targeting the five feature genes were further analyzed by computational screen.