Berberine alleviates pulmonary hypertension through Trx1 and β-catenin signaling pathways in pulmonary artery smooth muscle cells

Abstract Pulmonary arterial hypertension (PAH) is closely associated with profound vascular remodeling, especially pulmonary arterial medial hypertrophy and muscularization, due to aberrant proliferation of pulmonary artery smooth muscle cells (PASMCs). Berberine, a drug commonly used to treat inflammation, may be a novel therapeutic option for PAH by improving pulmonary artery remodeling. The present study investigated whether berberine affected Trx1/β-catenin expression and/or activity and whether it could reduce the development of pulmonary hypertension in an experimental rat model and proliferation in human PASMCs (HPASMCs). The results showed that increased proliferation in hypoxia-induced healthy PASMCs or PAH PASMCs was associated with a significant increase in Trx1 and β-catenin expression. Treatment with the Trx1-specific inhibitor PX-12 significantly reduced pulmonary arterial pressure and vascular remodeling, as well as improved in vivo cardiac function and right ventricular hypertrophy, in Su/Hox-induced PAH rats. Berberine reversed right ventricular systolic pressure and right ventricular hypertrophy and decreased pulmonary vascular remodeling in the rats. Furthermore, berberine had an antiproliferative effect on hypoxia-induced HPASMC proliferation in a manner likely mediated by inhibiting Trx1 and its target gene β-catenin expression. Our work will help elucidate novel strategies for PAH treatment involving the traditional Chinese medicine berberine, and Trx1/β-catenin may be a promising therapeutic target.