Identification of key fatty acid metabolism-related genes in pulmonary arterial hypertension through bioinformatics analysis and experimental studies

Background Pulmonary arterial hypertension (PAH) is a clinical illness primarily defined by exertional dyspnea and exhaustion, leading to significant pathophysiological alterations in pulmonary arteries. Several causative factors have been reported, among which dysfunction of fatty acid (FA) metabolism in cardiac and pulmonary vessels has been identified as the cause of structural and functional abnormalities of pulmonary vessels. However, the precise pathophysiological mechanism of FA metabolism dysfunction in PAH remains incompletely studied. Methods This study analyzed the differentially expressed genes (DEGs) in the PAH dataset (GSE117261) acquired from the Gene Expression Omnibus (GEO) database using the limma package in R. Furthermore, these DEGs were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. The DEGs that overlapped with FA metabolism genes were identified. Moreover, hub FA metabolism-related genes were determined via the following machine learning algorithms: support vector machine with recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression. The acquired hub genes were validated in PAH patients’ blood samples and the human pulmonary artery smooth muscle cells (HPASMCs). In addition, the association of key gene levels with mean pulmonary artery pressure (mPAP) of PAH patients was identified via Pearson correlation analysis. Results In total, 419 (221 upregulated and 198 downregulated) DEGs were determined. GO assessment showed that the DEGs were primarily linked with the positive modulation of cytokine synthesis, immune receptor activity, and collagen-containing extracellular matrix. KEGG analyses indicated substantial enrichment of coagulation and complement cascades and pathways related to malaria and leishmaniasis. Machine learning results showed that AKR1C3, CA2, FADS1, GPD1, PTGDS, and TBXAS1 were the key FA metabolism-related genes in PAH: expression of CA2, GPD1, and PTGDS was markedly upregulated, while that of AKR1C3, FADS1, and TBXAS1 was substantially downregulated in hypoxic HPASMCs, with similar results obtained in patients’ blood samples. Additionally, the levels of hub FA metabolism-linked genes in PAH patients’ peripheral blood correlated strongly with mPAP. Conclusions We have identified six key FA metabolism-related genes potentially involved in the pathogenesis of PAH that could prove to be important diagnostic and therapeutic markers.