YAP-mediated glycolysis promotes pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension.

Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) has been identified as a key enzyme regulating glycolysis. However, the molecular mechanisms underlying PFKFB3 regulation and glycolysis reprogramming in PAH remain unclear. Here, primary cultured pulmonary arterial smooth muscle cells (PASMCs) and monocrotaline-induced PAH rats were used to investigate these unknown mechanisms. We found that PFKFB3 expression and PASMC glycolysis were significantly increased in high mobility group box 1 (HMGB1)-treated cells, accompanied by the dephosphorylation and nuclear translocation of Yes-associated protein (YAP) via Rho-associated protein kinase signaling. Activation of YAP then acted as a transcriptional coactivator in conjunction with transcriptional enhancer activator domain 1, bolstering the transcription of the crucial glycolytic enzyme PFKFB3, consequently amplifying PASMC glycolysis. Rho-associated protein kinase inhibition, YAP or PFKFB3 knockdown, or glycolysis blockage diminished HMGB1-induced PASMC proliferation. In rats with monocrotaline-induced PAH, interventions such as inhibiting HMGB1 with glycyrrhizin, suppressing YAP activation with verteporfin, and targeting PFKFB3 with 3-PO effectively halted PAH progression. Our findings suggest that targeting the HMGB1-YAP-PFKFB3-glycolytic pathway is a promising strategy for preventing and treating PAH.