Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou 325000, China.
Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Biomed Pharmacother. 2024 Aug;177:117023. doi: 10.1016/j.biopha.2024.117023. Epub 2024 Jun 21.
Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) is an important manifestation and mechanism of pulmonary vascular remodeling. Resolvin D1 (RvD1) is an endogenous lipid mediator promoting the resolution of inflammation. However, the role of RvD1 on EndMT in PH remains unknown. Here, we aimed to investigate the effect and mechanisms of RvD1 on the treatment of PH. We showed that RvD1 and its receptor FPR2 expression were markedly decreased in PH patients and both chronic hypoxia-induced PH (CH-PH) and sugen 5416/hypoxia-induced PH (SuHx-PH) mice models. RvD1 treatment decreased right ventricular systolic pressure (RVSP) and alleviated right ventricular function, and reduced pulmonary vascular remodeling and collagen deposition in the perivascular of both two PH mice models. Then, RvD1 inhibited EndMT in both the lungs of PH mice models and primary cultured human umbilical vein endothelial cells (HUVECs) treated with TGF-β and IL-1β. Moreover, RvD1 inhibited EndMT by downregulating Smad2/3 phosphorylation in vivo and in vitro via FPR2. In conclusion, our date suggest that RvD1/FPR2 axis prevent experimental PH by inhibiting endothelial-mensenchymal-transition and may be a therapeutic target for PH.
肺动脉高压（PH）是一种以肺血管重构为特征的危及生命的疾病。内皮-间充质转化（EndMT）是肺血管重构的重要表现和机制。解析素 D1（RvD1）是一种内源性脂质介质，可促进炎症消退。然而，RvD1 对 PH 中 EndMT 的作用尚不清楚。在这里，我们旨在研究 RvD1 对 PH 治疗的作用和机制。我们表明，RvD1 及其受体 FPR2 的表达在 PH 患者以及慢性低氧诱导的 PH（CH-PH）和 Sugen 5416/低氧诱导的 PH（SuHx-PH）小鼠模型中均显著降低。RvD1 治疗可降低右心室收缩压（RVSP）并改善右心室功能，并减轻两种 PH 小鼠模型的肺血管重构和血管周围胶原沉积。然后，RvD1 抑制了 PH 小鼠模型肺和 TGF-β和 IL-1β处理的原代人脐静脉内皮细胞（HUVEC）中的 EndMT。此外，RvD1 通过 FPR2 在体内和体外下调 Smad2/3 磷酸化来抑制 EndMT。总之，我们的数据表明，RvD1/FPR2 轴通过抑制内皮-间充质转化来预防实验性 PH，可能是 PH 的治疗靶点。
