1. Department of Respiratory and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215000, P.R. China.
2. Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
3. Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China.
4. Department of Respiratory Medicine, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China.
5. Department of Respiratory and Critical Care Medicine, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou 213003, P.R. China.
*These authors have contributed equally to this work and share first authorship
Pulmonary arterial hypertension (PAH) characterized by pulmonary vascular remodeling is a lethal disease. Paeoniflorin (PF) is a monoterpene glycoside with numerous beneficial functions, such as vasodilation, anti-inflammation and immunomodulation. This study aims to investigate the effects of PF on monocrotaline (MCT)-induced PAH rats. Our data showed that both prophylactic or therapeutic administration of PF alleviated MCT-induced increasing of right ventricular systolic pressure (RVSP), prevented right ventricle hypertrophy and pulmonary arterial remodeling, as well as inhibited inflammatory cell infiltration around pulmonary arteries. Meanwhile, PF blocked MCT-induced endothelial-mesenchymal transition (EndMT) as indicated by the restored expression of endothelial markers in lung. Moreover, PF inhibited MCT-induced down-regulation of bone morphogenetic protein receptor 2 (BMPR2) and suppressed MCT-induced phosphorylation of transforming growth factor-β (TGFβ) activated kinase 1 (TAK1) in vivo. In vitro studies indicated that PF prevented human pulmonary arterial smooth muscle cells (PASMCs) from platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferation and migration. PF also partially reversed TGFβ1, interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) co-stimulated endothelial-to-mesenchymal transition (EndMT) in cultured human pulmonary artery endothelial cells (HPAECs). Signaling pathway analysis demonstrated that the underlying mechanism might be associated with the inhibition of TAK1-MAPK/NF-κB pathways. Taken together, our results suggested that PF could be a potential drug for the treatment of PAH.
Keywords: paeoniflorin, pulmonary arterial hypertension, pulmonary vascular remodeling, endothelial-to-mesenchymal transition, smooth muscle cells, monocrotaline