Adenosine monophosphate, one metabolite from lower respiratory tract, promotes the progression of pulmonary arterial hypertension through the PI3K/AKT signaling pathway in pediatric with congenital heart disease

Background The PI3K/AKT pathway is a crucial signaling pathway linked to cell growth and death in pulmonary arterial hypertension (PAH). In this study, we profiled the metabolic changes associated with PAH and investigated the role of adenosine monophosphate (AMP) in regulating PI3K/AKT signaling during PAH progression. Methods The metabolites in the lung tissue lavage fluids from PAH patients and healthy controls were subjected to metabolite profiling. Human pulmonary artery endothelial cells (HPAECs) were subjected to AMP treatment, and the cell phenotype changes were assessed by CCK-8 proliferation assay, migration assay and in vitro tube formation assay. The impacts of AMP on PI3K/AKT pathway and the epithelial-mesenchymal transition (EMT) in HPAECs were examined by Western blot. A rat model of PAH was established to evaluate the roles of AMP and PI3K/AKT signaling in PAH progression. Results We identified AMP as an upregulated metabolite in the lung tissue lavage fluids of PAH patients. AMP treatment inhibited the cell growth and angiogenic potential of HPAECs, while the AMP enhanced the EMT and migration in HPAECs. AMP treatment increased the phosphorylation levels of PI3K, AKT and mTOR in HPAECs. PI3K knockdown could reverse the effects of AMP on HPAECs. In the rat model of PAH, AMP administration aggravated the fibrosis of pulmonary artery by augmenting PI3K/AKT signaling, which could be alleviated by PI3K inhibitor. Conclusion Our study showed that AMP promotes PAH progression by regulating the PI3K/AKT signaling pathway and inducing EMT in pulmonary artery endothelial cells. Targeting AMP/PI3K/AKT signaling could be employed as strategy to alleviate PAH.