Hypoxia represses FOXF1 in lung endothelial cells through HIF-1α.
Hypoxia represses FOXF1 in lung endothelial cells through HIF-1α.
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缺氧通过HIF-1α抑制肺内皮细胞FOXF 1表达
DOI：
10.3389/fphys.2023.1309155
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发表时间：
2023
影响因子：
4
通讯作者：
Kalin, Tanya V.
中科院分区：
文献类型：
--
作者：
Acharya, Anusha;Bian, Fenghua;Gomez-Arroyo, Jose;Wagner, Kimberly A.;Kalinichenko, Vladimir V.;Kalin, Tanya V.
前言：Forkhead Box F1(FOXF1)转录因子在胚胎发育和肺损伤修复过程中发挥着重要的肺血管生成作用。肺损伤后内皮细胞FOXF1表达减少，但损伤肺内皮细胞FOXF1转录本变化的分子机制尚不清楚。方法：我们利用受损小鼠肺组织、低氧处理小鼠肺内皮细胞FACS分选和诊断为低氧性呼吸衰竭患者的数据进行免疫染色，以证明低氧与FOXF1表达降低有关。体外培养内皮细胞诱导低氧，探讨低氧抑制FOXF1基因表达的上游分子机制。结果：博莱霉素性肺损伤可引起小鼠肺组织缺氧，其机制与Foxf1表达减少有关。人FOXF1基因在诊断为低氧性呼吸衰竭的患者肺组织中表达降低。暴露在低氧环境中的小鼠肺组织和FACS分类的肺内皮细胞中Foxf1的表达减少。在体外，低氧(1%O2)或氯化钴(II)处理增加了三种内皮细胞系HIF-1α的蛋白水平，但抑制了FOXF1的表达。在培养的内皮细胞中过表达HIF-1α足以抑制FOXF1的表达。SiRNA介导的缺氧诱导因子-1α缺失可阻止低氧或氯化钴处理后foxf1基因表达的下调。结论：缺氧可抑制血管内皮细胞FOXF1的表达，其抑制作用依赖于HIF-1α。我们的数据表明，通过基因治疗对内皮细胞特异性抑制缺氧诱导因子-1α可以考虑恢复FOXF1，改善严重肺损伤患者的肺修复。
Introduction: Forkhead Box F1 (FOXF1) transcription factor plays a critical role in lung angiogenesis during embryonic development and lung repair after injury. FOXF1 expression is decreased in endothelial cells after lung injury; however, molecular mechanisms responsible for the FOXF1 transcript changes in injured lung endothelium remain unknown. Methods: We used immunostaining of injured mouse lung tissues, FACS-sorted lung endothelial cells from hypoxia-treated mice, and data from patients diagnosed with hypoxemic respiratory failure to demonstrate that hypoxia is associated with decreased FOXF1 expression. Endothelial cell cultures were used to induce hypoxia in vitro and identify the upstream molecular mechanism through which hypoxia inhibits FOXF1 gene expression. Results: Bleomycin-induced lung injury induced hypoxia in the mouse lung tissue which was associated with decreased Foxf1 expression. Human FOXF1 mRNA was decreased in the lungs of patients diagnosed with hypoxemic respiratory failure. Mice exposed to hypoxia exhibited reduced Foxf1 expression in the lung tissue and FACS-sorted lung endothelial cells. In vitro, hypoxia (1% of O2) or treatment with cobalt (II) chloride increased HIF-1α protein levels but inhibited FOXF1 expression in three endothelial cell lines. Overexpression of HIF-1α in cultured endothelial cells was sufficient to inhibit Foxf1 expression. siRNA-mediated depletion of HIF-1α prevented the downregulation of Foxf1 gene expression after hypoxia or cobalt (II) chloride treatment. Conclusion: Hypoxia inhibits FOXF1 expression in endothelial cells in a HIF-1α dependent manner. Our data suggest that endothelial cell-specific inhibition of HIF-1α via gene therapy can be considered to restore FOXF1 and improve lung repair in patients with severe lung injury.
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