Abstract Body (Do not enter title and authors here): Objective: Pulmonary Arterial Hypertension (PAH) is a fatal disease with high mortality rates and late diagnosis, currently lacking complete cure. Metabolic abnormalities play a crucial role in the pathophysiological process of pulmonary vascular remodeling. This study aimed to identify metabolic-related genes that may play important roles in PAH and analyze their expression and function and the clinical significance.
Methods: Transcriptomic data were retrieved from the GEO database, including tissue transcriptome data (GSE113439, GSE53408, GSE198618) and single-cell transcriptome data (GSE210248, GSE203274); "limma" and "DEseq2" packages were used to identify differentially expressed genes (DEGs); By WGCNA and Boruta algorithm, we identified feature genes related to PAH; Transcription factor network analysis was analyzed using the "RTN" package; Single-cell and single-nucleus transcriptome data were analyzed using the Seurat pipeline; Concentration of key genes’ protein level in PAH were evaluated using ELISA.
Results: The study found increased glycolysis, disrupted carnitine shuttle pathway, enhanced fatty acid degradation, decreased oxidative phosphorylation, and augmented polyamine synthesis in PAH. PIGN, SLC25A24, RPL5, PIK3CA, PIK3CB, DNM1L, SETD2, TPH1, ITPR2, PRKAA1, PTPN11, and PDK4 were identified as metabolic-related genes associated with PAH. PDK4 was significantly increased in pulmonary artery endothelial cells (PAECs) and right ventricular tissues of decompensated right heart failure, mainly expressed in cardiomyocytes. PDK4 was significantly elevated in the PAH group (control group: 4.15 ± 0.53 ng/ml; idiopathic pulmonary arterial hypertension group: 5.28 ± 0.77 ng/ml, p-value <0.001), and showed linear correlations with mean pulmonary artery pressure (r=0.51, p=0.00033) and pulmonary vascular resistance (r=0.44, p=0.0019).
Conclusion: This study provides important insights into the role of metabolic reprogramming and mitochondrial dysfunction in the pathogenesis of PAH, identifies 12 potential pathogenic regulatory factors related to metabolism, and suggests that PDK4 is strongly correlated with hemodynamic parameters of the disease, potentially participating in PAH and cardiac remodeling under right heart overload.