Attenuation of the AMPK–ACC–MCoA negative feedback on CPT1 leads to PASMC hyperproliferation in PAH

The pathogenic contribution of pulmonary artery smooth muscle cells (PASMCs) to pulmonary arterial hypertension (PAH) stems primarily from their abnormal proliferative activity. PAH is associated with dysregulated fatty acid metabolism, and carnitine palmitoyltransferase 1 (CPT1) is a key regulator of fatty acid metabolism. Previous research indicated that CPT1 enhanced the proliferation of pulmonary artery smooth muscle cells (PASMCs) via the adenosine monophosphate-activated protein kinase (AMPK)-p53-p21 signaling pathway. However, it remains unclear how CPT1 continuously activates AMPK without succumbing to malonyl-CoA (MCoA)-mediated inhibition. In this study, we examined the regulation of CPT1 and its impact on PASMC proliferation under PAH-related stimuli. We found that platelet-derived growth factor (PDGF)-BB up-regulated the expression of CPT1, down-regulated the phosphorylation levels of AMPK and acetyl-CoA carboxylase 1 (ACC1), and promoted the proliferation of PASMCs. The CPT1 inhibitor Etomoxir (Eto) reversed these effects. The AMPK agonist Metformin (Met) enhanced the phosphorylation of AMPK and ACC1 while upregulating CPT1 expression, and inhibited the proliferation of PASMCs. MCoA inhibited the expression of CPT1 and simultaneously up-regulated the phosphorylation levels of AMPK and ACC1. However, in PDGF-induced proliferating PASMCs, AMPK/ACC1 phosphorylation and CPT1 expression did not show significant changes after MCoA intervention, suggesting that the negative feedback inhibition of CPT1 by MCoA was weakened. Collectively, these findings suggest that modulation of CPT1 sensitivity to MCoA negative feedback could represent a potential therapeutic target in PAH.