Resolvin E1对小鼠肺动脉高压的作用及机制研究

Pulmonary hypertension (PH) is characterized by excessive proliferation in pulmonary vascular smooth muscle, which caused pulmonary vascular remodeling. Resolvin E1, which generates from omega-3 polyunsaturated fatty acids (PUFAs), plays a wide range role of anti-inflammatory effects through acting directly on inflammatory cells. It can also acts on non-inflammatory cells, such as smooth muscle cell, affecting its proliferation and migration processes. The exact role of RvE1 in PH remains unclear. Our previous studies have found that: RvE1 can protect against hypoxic-induced pulmonary hypertension by reducing the proliferation level of pulmonary artery smooth muscle cells through increase phosphorylation of yes-associated protein 1 (YAP). We hypothesize that: RvE1 may ameliorate hypoxic-induced PH in mice through Hippo-YAP signaling pathway. In order to verify this hypothesis, we plan to use ChemR23F/FSM22αCre and BLT1F/FSM22αCre mice, to reveal the receptor mediated by RvE1 in the protective effect on hypoxia-induced PH in mice; to explore whether RvE1 reduces PASMCs proliferation through Hippo signaling pathways; to investigate the protein kinase which promotes YAP phosphorylation; to explore the downstream transcription factor that bind to YAP. These results provide, to our knowledge, the first empirical evidence that RvE1-ChemR23 signaling axis as a novel target for treating PH.

肺动脉平滑肌细胞（PASMCs）过度增殖导致的血管重塑，是肺动脉高压（PH）重要的病理特征。炎性介质Resolvin E1 (RvE1)可以作用于炎性细胞，促进炎症消退；也可以调控非炎性细胞（如平滑肌细胞）的功能，目前RvE1在PH中的作用仍不清楚。我们前期实验发现：RvE1可以显著改善小鼠低氧诱导的PH，降低PASMCs的增殖水平，提高Hippo信号通路中关键效应蛋白YAP的磷酸化。因此我们推测：RvE1可能通过Hippo-YAP信号通路影响小鼠低氧诱导的PH。为了验证这一假设，本研究构建ChemR23F/FSM22αCre和BLT1F/FSM22αCre小鼠，揭示RvE1发挥对小鼠低氧诱导PH保护作用所通过的受体；探究RvE1是否通过Hippo信号通路降低PASMCs增殖水平；探究RvE1促进YAP磷酸化所通过的蛋白激酶；探究下游和YAP结合的转录因子。该研究为PH的治疗提供新的靶点。

肺动脉高压(PH)是一种以严重的肺血管壁重塑和血管周围炎症为特征的毁灭性疾病。Resolvin E1 (RvE1)是一种促进炎症消解的脂质介质，对多种炎症性疾病具有保护作用。本课题通过对低氧+SU5416(HySu)诱导的小鼠PH模型和野百合碱诱导的大鼠PH模型以及从PH患者中收集肺组织和血浆样本，检测发现：特发性PH患者的血浆和PH实验啮齿动物模型的肺中，RvE1的生成减少；在缺氧暴露的小鼠肺动脉平滑肌细胞(PASMCs)、PH啮齿动物和特发性PH患者的肺动脉中，ChemR23的表达明显下调。进而通过多种分子生物学和组学手段，发现RvE1可以降低PH进程中肺血管周围炎性细胞的浸润水平降低炎症反应；同时降低PASMCs的增殖水平从而延缓PH的进程；血管平滑肌细胞中ChemR23的缺失消除了RvE1对HySU诱导的小鼠PH的保护作用。在机制上，RvE1/ChemR23轴通过抑制增殖性Wnt7a/β-catenin信号通路抑制缺氧诱导的PASMC增殖。RvE1激活ChemR23通过抑制PKA介导的Egr2 Ser349位点磷酸化降低PASMCs中Wnt7a的表达。因此，RvE1/ChemR23轴通过调节PASMCs中的Wnt7a/β-catenin信号通路抑制PH进程，并有望作为PH治疗的新靶点。