Novel FOXF1-Stabilizing Compound TanFe Stimulates Lung Angiogenesis in Alveolar Capillary Dysplasia.
Novel FOXF1-Stabilizing Compound TanFe Stimulates Lung Angiogenesis in Alveolar Capillary Dysplasia.
复制标题
新型 FOXF1 稳定化合物 TanFe 刺激肺泡毛细血管发育不良的肺血管生成。
DOI：
10.1164/rccm.202207-1332oc
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发表时间：
2023
影响因子：
24.7
通讯作者：
Kalinichenko,VladimirV
中科院分区：
文献类型：
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作者：
Pradhan,Arun;Che,Lixiao;Ustiyan,Vladimir;Reza,AbidA;Pek,NicoleM;Zhang,Yufang;Alber,AndreaB;Kalin,TimothyR;Wambach,JenniferA;Gu,Mingxia;Kotton,DarrellN;Siefert,MatthewE;Ziady,AssemG;Kalin,TanyaV;Kalinichenko,VladimirV
理由：肺泡毛细血管发育不良伴肺静脉错位 (ACDMPV) 与 FOXF1（Forkhead Box F1）基因的杂合突变有关，FOXF1 基因是肺血管发育的关键转录调节因子。除肺移植外，ACDMPV 尚无有效治疗方法，迫切需要新的激活 FOXF1 信号传导的药物。目的：鉴定刺激 FOXF1 信号传导的小分子化合物。方法：我们使用质谱、免疫沉淀和体外泛素化测定来鉴定 TanFe（核 FOXF1 表达的跨细胞激活剂），这是一种来自腈基的小分子化合物，可稳定 FOXF1细胞中的蛋白质。 TanFe 的功效在 ACDMPV 和急性肺损伤小鼠模型以及源自 ACDMPV 患者诱导多能干细胞的人血管类器官中进行了测试。测量和主要结果：我们确定 HECTD1 是一种 E3 泛素连接酶，参与 FOXF1 蛋白的泛素化和降解。 TanFe 化合物破坏了 FOXF1-HECTD1 蛋白质-蛋白质相互作用，并降低了体外肺内皮细胞中 FOXF1 蛋白质的泛素化。 TanFe 增加 LPS 损伤小鼠肺部 FOXF1 及其靶基因 Flk1、Flt1 和 Cdh5 的蛋白浓度，降低内皮通透性并抑制肺部炎症。用 TanFe 治疗怀孕小鼠可增加 Foxf1+/- 胚胎肺部的 FOXF1 蛋白浓度，刺激新生肺血管生成，并完全防止 Foxf1+/- 小鼠出生后的死亡率。 TanFe 增加了 FOXF1 缺失 ACDMPV 患者诱导多能干细胞来源的人血管类器官的血管生成。结论：TanFe 是一种新型 FOXF1 激活剂，为治疗 ACDMPV 和其他新生儿肺血管疾病提供了新的治疗候选者。
Rationale:Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is linked to heterozygous mutations in theFOXF1(Forkhead Box F1) gene, a key transcriptional regulator of pulmonary vascular development. There are no effective treatments for ACDMPV other than lung transplant, and new pharmacological agents activating FOXF1 signaling are urgently needed.Objectives:Identify-small molecule compounds that stimulate FOXF1 signaling.Methods:We used mass spectrometry, immunoprecipitation, and thein vitroubiquitination assay to identify TanFe (transcellular activator of nuclear FOXF1 expression), a small-molecule compound from the nitrile group, which stabilizes the FOXF1 protein in the cell. The efficacy of TanFe was tested in mouse models of ACDMPV and acute lung injury and in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV.Measurements and Main Results:We identified HECTD1 as an E3 ubiquitin ligase involved in ubiquitination and degradation of the FOXF1 protein. The TanFe compound disrupted FOXF1–HECTD1 protein–protein interactions and decreased ubiquitination of the FOXF1 protein in pulmonary endothelial cellsin vitro. TanFe increased protein concentrations of FOXF1 and its target genesFlk1,Flt1, andCdh5in LPS-injured mouse lungs, decreasing endothelial permeability and inhibiting lung inflammation. Treatment of pregnant mice with TanFe increased FOXF1 protein concentrations in lungs ofFoxf1+/−embryos, stimulated neonatal lung angiogenesis, and completely prevented the mortality ofFoxf1+/−mice after birth. TanFe increased angiogenesis in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV withFOXF1deletion.Conclusions:TanFe is a novel activator of FOXF1, providing a new therapeutic candidate for treatment of ACDMPV and other neonatal pulmonary vascular diseases.