Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.
Department of Respiratory and Critical Care Medicine, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou 213003, People's Republic of China.
Drug Des Devel Ther. 2020 Mar 19;14:1191-1202. doi: 10.2147/DDDT.S235207. eCollection 2020.
Endothelial cells dysfunction is one of the hallmark pathogenic features of pulmonary arterial hypertension (PAH). Paeoniflorin (PF) is a monoterpene glycoside with endothelial protection, vasodilation, antifibrotic, anti-inflammatory and antioxidative properties. However, the effects of PF on PAH remain unknown.
Here, we investigated the efficacy of PF in the SU5416/hypoxia (SuHx) rat model of PAH. Human pulmonary arterial endothelial cells (HPAECs) were exposed to 1% O with or without PF treatment.
Hemodynamics analysis showed that prophylactic treatment with PF (300 mg/kg i.g. daily for 21 days) significantly inhibited chronic hypoxia/SU5416-induced elevations of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index in rats. Meanwhile, PF significantly reduced pulmonary vascular remodeling, as well as alleviated collagen deposition in lungs and right ventricles in SuHx rats. Additionally, PF inhibited SuHx-induced down-regulation of endothelial marker (vascular endothelial cadherin) and up-regulation of mesenchymal markers (fibronectin and vimentin) in lung, suggesting that PF could inhibit SuHx-induced endothelial-to-mesenchymal transition (EndMT) in lung. Further in vitro studies confirmed that PF treatment suppressed hypoxia-induced EndMT in HPAECs, which was abolished by the knockdown of bone morphogenetic protein receptor type 2 (BMPR2) in HPAECs.
Taken together, our findings suggest that PF ameliorates BMPR2 down-regulation-mediated EndMT and thereafter alleviates SuHx-induced PAH in rats.
内皮细胞功能障碍是肺动脉高压（PAH）的主要致病特征之一。芍药苷（PF）是一种具有内皮保护、血管扩张、抗纤维化、抗炎和抗氧化作用的单萜糖苷。然而，PF 对 PAH 的影响尚不清楚。
在这里，我们研究了 PF 在 SU5416/缺氧（SuHx）大鼠 PAH 模型中的疗效。将人肺动脉内皮细胞（HPAEC）暴露于 1% O2 中，或用 PF 处理。
血流动力学分析表明，PF（每天 300mg/kg 口服 21 天）的预防性治疗显著抑制了慢性缺氧/SU5416 诱导的大鼠右心室收缩压（RVSP）和右心室肥厚指数升高。同时，PF 显著减轻 SuHx 大鼠的肺血管重构，并减轻肺和右心室中的胶原沉积。此外，PF 抑制了 SuHx 诱导的肺内皮标志物（血管内皮钙黏蛋白）下调和间质标志物（纤连蛋白和波形蛋白）上调，表明 PF 可抑制 SuHx 诱导的肺内皮-间质转化（EndMT）。进一步的体外研究证实，PF 治疗抑制了 HPAECs 中的缺氧诱导的 EndMT，而在 HPAECs 中敲低骨形态发生蛋白受体 2（BMPR2）则消除了这种作用。
综上所述，我们的研究结果表明，PF 改善了 BMPR2 下调介导的 EndMT，并随后缓解了 SuHx 诱导的大鼠 PAH。
