Ursolic Acid Improves Monocrotaline-Induced Right Ventricular Remodeling by Regulating Metabolism

Abstract: Pulmonary arterial hypertension (PAH) is a progressive and malignant disease characterized by pulmonary small arteries and right ventricle (RV) remodeling that can lead to severe RV dysfunction and death. The current therapeutic targets for RV dysfunction, which is strongly linked to mortality, are far from adequate. Therefore, we investigated the effect of ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, on PAH-induced RV remodeling and its underlying mechanism. We established a PAH model by injecting Sprague Dawley rats with monocrotaline (MCT, 60 mg/kg, ip), as verified by echocardiography and hemodynamic examination. Proteomic analysis was performed on RV samples using a Q Exactive high-field mass spectrometer, followed by KEGG enrichment analysis. The effect of 4 weeks of UA (50 mg/kg) treatment on RV remodeling was explored based on ultrasound, hemodynamic parameters, and histological changes, with the mechanism verified in vivo and in vitro by qRT-PCR and western blotting. RV hypertrophy, fibrosis, increased apoptosis, and abnormal metabolism were induced by MCT and suppressed by UA via a mechanism that changed the expression of key markers. UA also attenuated the Phenylephrine-induced hypertrophy of neonatal rat ventricular myocytes and upregulated peroxisome proliferator-activated receptor-alpha (PPARα), a key fatty acid metabolism regulator, and its downstream factor carnitine palmitoyl transferase 1b. In conclusion, UA exerts beneficial effects on PAH-induced RV dysfunction and remodeling by regulating PPARα-dependent fatty acid metabolism.