Resolvin E1 Attenuates Pulmonary Hypertension by Suppressing Wnt7a/β-Catenin Signaling
Resolvin E1 Attenuates Pulmonary Hypertension by Suppressing Wnt7a/β-Catenin Signaling
复制标题
Resolvin E1 通过抑制 Wnt7a/β-连环蛋白信号传导减轻肺动脉高压
DOI：
10.1161/hypertensionaha.121.17809
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发表时间：
2021-12-01
期刊：
影响因子：
8.3
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Liu, Guizhu;Wan, Naifu;Wang, Jian
补充数字内容可在正文中找到。肺动脉高压(PAH)是一种以严重的肺血管壁重构和血管周围炎症为特征的破坏性疾病。RvE1是一种促分解脂介质，对多种炎症性疾病具有保护作用。然而，RvE1在PAH发生中的作用仍有待确定。我们的目的是研究RvE1是否对PAH有治疗作用，如果是，则阐明其作用的分子机制。采用低氧+SU5416诱导的小鼠肺动脉高压模型和野百合碱诱导的大鼠肺动脉高压模型，观察RvE1的治疗作用。采集PAH患者肺组织和血浆标本，检测RvE1的产生及其受体趋化素样受体1(ChemR23)的表达。我们观察到，特发性PAH患者的血浆和实验性PH啮齿动物模型的肺组织中RvE1的生成减少。在低氧暴露的小鼠肺动脉平滑肌细胞(PASMCs)和PH啮齿类动物及特发性PAH患者的肺动脉中，ChemR23的表达明显下调。RvE1治疗通过抑制PASMC的增殖减轻了雄性和雌性啮齿动物的实验性PH。血管SMC中ChemR23的缺失取消了RvE1对低氧+SU5416诱导的小鼠PAH的保护作用。在机制上，RvE_1/ChemR_(23)轴通过抑制增殖的无翅型MMTV整合位点家族成员7a/β-catenin信号通路，抑制缺氧诱导的PASMC增殖。通过抑制蛋白激酶A介导的早期生长反应2(早期生长反应2)在Ser349的磷酸化，RvE1激活ChemR23降低了PASMCs中无翅型MMTV整合位点家族成员7a的表达。因此，RvE_1/ChemR_(23)轴通过调节PASMC中的无翅型MMTV整合位点家族成员7a/β-catenin信号来抑制实验性的肺动脉高压，可作为治疗肺动脉高压的靶点。
Supplemental Digital Content is available in the text. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by severe pulmonary vascular wall remodeling and perivascular inflammation. Resolvin E1 (RvE1), a proresolving lipid mediator, has protective effects against various inflammatory diseases. However, the effect of RvE1 on PAH development remains to be determined. We aimed to investigate whether RvE1 has a therapeutic effect on PAH and, if so, to elucidate the molecular mechanisms underlying its effects. A hypoxia+SU5416-induced mouse model of pulmonary hypertension (PH) and an monocrotaline-induced rat model of PH were used to test therapeutic effect of RvE1. Lung tissues and plasma samples were collected from patients with PAH and rodent models to examine RvE1 production and its receptor chemerin chemokine-like receptor 1 (ChemR23) expression. We observed that RvE1 generation was reduced in the plasma of patients with idiopathic PAH and in lungs from experimental rodent models of PH. ChemR23 expression was markedly downregulated in hypoxia-exposed mouse pulmonary artery smooth muscle cells (PASMCs) and pulmonary arteries from PH rodents and patients with idiopathic PAH. RvE1 treatment alleviated experimental PH in both male and female rodents by inhibiting PASMC proliferation. Deletion of ChemR23 in vascular SMCs abolished the protective effect of RvE1 against hypoxia+SU5416-induced PAH in mice. Mechanistically, the RvE1/ChemR23 axis suppressed hypoxia-induced PASMC proliferation by inhibiting proliferative wingless-type MMTV integration site family member 7a/β-catenin signaling. Activation of ChemR23 by RvE1 diminished wingless-type MMTV integration site family member 7a expression in PASMCs by inhibiting protein kinase A-mediated Egr2 (early growth response 2) phosphorylation at Ser349. Thus, the RvE1/ChemR23 axis represses experimental PAH by modulating wingless-type MMTV integration site family member 7a/β-catenin signaling in PASMCs and may serve as a therapeutic target for the management of PAH.