Sitosterol-Beta mitigates pulmonary hypertension by targeting SPHK1 in mice

Sitosterol-Beta alleviated hypoxia and SU5416-induced pulmonary hypertension in mice. • Sitosterol-Beta suppressed excessive proliferation and migration of pulmonary artery smooth muscle cells. • Sitosterol-Beta inhibited SPHK1 expression and S1P production in pulmonary artery smooth muscle cells. • Sitosterol-Beta blocked S1P-mediated inflammation in macrophages. Pulmonary hypertension (PH) is an irreversible and life-threatening disease, characterized by sustainedly elevated pulmonary arterial pressure. The excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and perivascular inflammation are primary pathological features. Sitosterol-Beta is a phytosterol with extensive anti-inflammatory roles. This study aims to investigate the effects of Sitosterol-Beta on PH. In our study, the PH was induced in mouse by chronic hypoxia insult (10% O 2 ) and subcutaneous injection of vascular endothelial growth factor receptor inhibitor SU5416, and Sitosterol-Beta was delivered into mouse via orally taken. Mouse primary PASMCs were cultured with 1% O 2 to mimic hypoxic condition, and treated with Sitosterol-Beta. The results revealed that Sitosterol-Beta restrained PH-induced right ventricular systolic pressure increase, right ventricular hypertrophy, thickening and fibrosis of pulmonary artery, and perivascular inflammation. Sphingosine kinase 1 (SPHK1) was screened as the potential target of Sitosterol-Beta. Sitosterol-Beta inhibited SPHK1 expression and sphingosine-1-phosphate (S1P) production in lung. In vitro , Sitosterol-Beta suppressed hypoxia-induced excessive proliferation, migration and endothelial-to-mesenchymal transition of primary PASMCs, and blocked S1P-mediated inflammation in macrophages. The effects of Sitosterol-Beta on PASMCs were abrogated by overexpression of SPHK1. In conclusion, this study demonstrated that Sitosterol-Beta improved PH in mouse by targeting SPHK1, which may provide novel insights for prevention and therapy of PH. Download: Download high-res image (275KB) Download: Download full-size image