Abstract
Salidroside (SAL), an active component derived from the traditional Chinese medicine Rhodiola, has been demonstrated to have protective effects on models of pulmonary arterial hypertension (PAH), though its mechanisms have not been fully elucidated. This study aims to investigate the therapeutic effects of SAL on a PAH rat model induced by monocrotaline, as well as its impact on oxidative stress and inflammatory responses in lung tissues, by employing immunohistochemistry, ELISA, Western blot, and untargeted metabolomics approaches. The results indicated that SAL treatment significantly reduced pulmonary artery pressure and right ventricular compensatory hypertrophy, ameliorated pulmonary vascular wall thickening and remodeling, and alleviated oxidative stress and inflammatory responses in the lungs of PAH rats. The underlying mechanisms were associated with the promotion of endogenous nitric oxide (NO) synthesis and bioavailability. Furthermore, metabolomic analysis revealed metabolic dysregulation in the PAH rat model, characterized by disturbances in arginine, proline, citrate, aminoacyl-tRNA, glycerophospholipid, riboflavin, and serine metabolism. SAL intervention effectively restored metabolic balance in the pulmonary artery of PAH rats. The findings of this study suggest that SAL exerts its anti-PAH effects by improving arginine metabolism dysregulation, promoting endogenous NO synthesis and bioactivity utilization, thereby mitigating lung tissue damage and improving pulmonary vascular wall thickening and remodeling.