Metabolomics-based mechanism exploration of pulmonary arterial hypertension pathogenesis: novel lessons from explanted human lungs

Pulmonary arterial hypertension has led to global health and social problems, but the pathogenic mechanism has not been fully elucidated. Dysregulated metabolism is closely associated with the pathogenesis of pulmonary arterial hypertension. Here, we investigated metabolic profile shifts to reveal the molecular mechanisms underlying pulmonary hypertension. Explanted lung tissues from 13 idiopathic pulmonary arterial hypertension patients, 5 pulmonary arterial hypertension associated with congenital heart disease patients, and 16 controls were collected for untargeted metabolomics analysis with liquid chromatography coupled with tandem mass spectrometry. The KEGG database and MetaboAnalyst 5.0 were used for pathway analysis. A Cox survival analysis model was applied to evaluate the predictive value of metabolites on prognosis. Protein expression levels in human and rat pulmonary arterial hypertension lungs and hypoxia-exposed human pulmonary artery smooth muscle cells were detected by Western blotting to study the molecular mechanisms. Significant differences in metabolites and metabolic pathways were identified among the pulmonary arterial hypertension subgroups and control tissues. The levels of spermine were positively correlated with the patients' cardiac output, and (2e)-2,5-dichloro-4-oxo-2-hexenedioic acid was positively correlated with the patients' serum creatinine levels. Patients with higher thymine levels had a better prognosis. Moreover, seven differential metabolites were associated with the AKT pathway. AKT pathway inactivation was confirmed in human and rat pulmonary hypertensive lungs and pulmonary artery smooth muscle cells exposed to hypoxia. Our findings provide the first metabolomics evidence for pulmonary arterial hypertension pathogenesis in human lungs and may contribute to the improvement in therapeutic strategies.