Metabolomics Based Mechanism Exploration of Pulmonary Arterial Hypertension pathogenesis: Novel Lessons from Explanted Lungs
Abstract Background: Metabolic pathways have been shown to participate in the pathogenesis of pulmonary arterial hypertension (PAH). We investigated the metabolic profile shifts to reveal molecular mechanisms underlying PAH. Methods: Explanted human lung tissues from 18 PAH patients were collected. The lung tissues far from the tumor from 16 lung cancer patients were taken as controls. Lung tissues were analyzed by LC-MS/MS based non-target metabolomics method. Pathway analysis was performed with KEGG database and MetaboAnalyst 5.0. Statistical analysis including partial least squares discriminant analysis (PLS-DA), Student’s t-test, Pearson’s correlation, Chi-square test and Fisher’s exact probability test were used. COX survival analysis model was applied to evaluate the predictive value of metabolites on prognosis. Protein expression levels were detected by Western blotting in human PAH lung tissues, rat monocrotaline-PAH lungs and hypoxia exposed human pulmonary artery smooth muscle cells (HPASMCs) to study the molecular mechanisms.Results: Significant differences in metabolites and metabolic pathways were identified among PAH subgroups and control tissues. Spermine levels were positively correlated with the patients' cardiac outputs (COs). Levels of (2e)-2,5-dichloro-4-oxo-2-hexenedioic acid were positively correlated with the patient's serum creatinine (Scr) levels. Patients with higher levels of thymine had a better prognosis. Moreover, 7 differential metabolites were associated with AKT pathway. AKT pathway inactivation was confirmed in human and rat PAH lungs and hypoxia exposed HPASMCs.Conclusions: Our findings provide the first metabolomics evidence for PAH pathogenesis by human lungs and may contribute to the improvement of therapeutic strategy.