FOXF1 减少与肺动脉高压相关的未修复 DNA 损伤。
Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension.
机构信息
Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.
Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.
出版信息
Nat Commun. 2023 Nov 21;14(1):7578. doi: 10.1038/s41467-023-43039-y.
Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm). Gene expression analysis of EC-Atm and EC-Bmpr2 lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2 mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.
肺动脉高压（PAH）是一种进行性疾病，其中肺动脉（PA）内皮细胞（EC）功能障碍与未修复的 DNA 损伤有关。BMPR2 是 PAH 的最常见遗传原因。我们报告说，在低氧（复氧）后，BMPR2 减少的人 PAEC 在室内空气中持续存在 DNA 损伤，EC 特异性缺失 Bmpr2 的小鼠（EC-Bmpr2）和持续性肺动脉高压也是如此。在 ATM 缺失的 PAEC 中观察到类似的发现，在 EC 中缺失 Atm 的小鼠（EC-Atm）中也是如此。EC-Atm 和 EC-Bmpr2 肺 EC 的基因表达分析显示 Foxf1 减少，Foxf1 是一种对肺 EC 具有选择性的转录因子。在对照 PAEC 中降低 FOXF1 会诱导 DNA 损伤和血管生成受损，而在 PAH PAEC 中转染 FOXF1 可修复 DNA 损伤并恢复血管生成。将 Foxf1 靶向递送至复氧的 EC-Bmpr2 小鼠可修复 DNA 损伤，诱导血管生成并逆转肺动脉高压。
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