This study aimed to evaluate the effects of limonin on pulmonary vascular abnormalities in hypoxia-induced PH rats and investigate its potential mechanisms.

     Male Sprague Dawley rats were put in a hypoxia chamber (10% O2) for 3 weeks to establish hypoxia-induced pulmonary hypertension (HPH) model, and then treated with limonin at the dose of 50 or 100 mg/kg for 2 weeks. We assessed the impact of limonin on mean pulmonary arterial pressure (mPAP), pulmonary vascular remodeling, and right ventricular hypertrophy. In vitro, we evaluated hypoxia-induced cellular proliferation, migration, and apoptosis of rat PASMCs. Proteins related to the AKT/Nrf2 signaling pathway were analyzed by western blotting and immunofluorescence assays. 

     Limonin significantly reduced hypoxia induced PH and pulmonary arterial remodeling in rats. Additionally, limonin prevented the proliferation and migration of PASMCs and induced the apoptosis of PASMCs. Furthermore, limonin suppressed the upregulation of phosphorylated AKT and nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. Both in vitro and in vivo experiments demonstrated that Nrf2 overexpression partially counteracted the effect of limonin. 

     In conclusion, limonin alleviated hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. The molecular mechanisms are related with AKT/Nrf2 signaling pathway in the lung.