Loss of Hif-2α Rescues the Hif-1α Deletion Phenotype of Neonatal Respiratory Distress In Mice.
Loss of Hif-2α Rescues the Hif-1α Deletion Phenotype of Neonatal Respiratory Distress In Mice.
复制标题
DOI：
10.1371/journal.pone.0139270
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
LaPres JJ
中科院分区：
文献类型：
--
作者：
Saini Y;Proper SP;Dornbos P;Greenwood KK;Kopec AK;Lynn SG;Grier E;Burgoon LD;Zacharewski TR;Thomas RS;Harkema JR;LaPres JJ
缺氧是一种到达身体组织的氧气减少的状态。在产前发育期间，胎儿经历局部缺氧，这对正常器官形成和存活至关重要。对氧可用性降低的反应主要由低氧诱导因子（HIF）调节，HIF是调节参与糖酵解、血管生成和红细胞生成的关键基因表达的转录因子家族。HIF-1α和HIF-2α是两种关键的亚型，在胚胎发育中很重要，并且可能参与肺形态发生。我们最近的研究表明，从E4.5开始，肺上皮细胞中Hif-1α的诱导性丢失导致分娩后1小时内死亡，症状类似于新生儿呼吸窘迫综合征（RDS）。除了Hif-1α外，Hif-2α也在发育中的肺中表达，尽管Hif-1α和Hif-2α在此背景下的重叠作用尚未完全了解。为了进一步研究Hif-2α在肺上皮中的独立作用及其改变Hif-1α介导的肺成熟的能力，我们产生了另外两种肺特异性诱导型Hif-α敲除模型（Hif-2α和Hif-1α+Hif-2α）。肺中Hif-2α的宫内丢失不会导致肺活力降低或可观察到的表型变化。更有趣的是，在Hif-1α和Hif-2α缺失后观察到的存活率表明，Hif-2α缺失能够挽救在Hif-1α缺陷幼崽中观察到的新生儿RDS表型。对这三种基因型肺组织的微阵列分析确定了几个因子，如Scd 1、Retlnγ和IL-1 r2，它们受两种HIF-α亚型的差异调节。此外，网络分析表明，HIF介导的肺发育变化的核心是对NF-κB、C/EBPα和c-MYC信号的调节。
Hypoxia is a state of decreased oxygen reaching the tissues of the body. During prenatal development, the fetus experiences localized occurrences of hypoxia that are essential for proper organogenesis and survival. The response to decreased oxygen availability is primarily regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that modulate the expression of key genes involved in glycolysis, angiogenesis, and erythropoiesis. HIF-1α and HIF-2α, two key isoforms, are important in embryonic development, and likely are involved in lung morphogenesis. We have recently shown that the inducible loss of Hif-1α in lung epithelium starting at E4.5 leads to death within an hour of parturition, with symptoms similar to neonatal respiratory distress syndrome (RDS). In addition to Hif-1α, Hif-2α is also expressed in the developing lung, although the overlapping roles of Hif-1α and Hif-2α in this context are not fully understood. To further investigate the independent role of Hif-2α in lung epithelium and its ability to alter Hif-1α-mediated lung maturation, we generated two additional lung-specific inducible Hif-α knockout models (Hif-2α and Hif-1α+Hif-2α). The intrauterine loss of Hif-2α in the lungs does not lead to decreased viability or observable phenotypic changes in the lung. More interestingly, survivability observed after the loss of both Hif-1α and Hif-2α suggests that the loss of Hif-2α is capable of rescuing the neonatal RDS phenotype seen in Hif-1α-deficient pups. Microarray analyses of lung tissue from these three genotypes identified several factors, such as Scd1, Retlnγ, and Il-1r2, which are differentially regulated by the two HIF-α isoforms. Moreover, network analysis suggests that modulation of hormone-mediated, NF-κB, C/EBPα, and c-MYC signaling are central to HIF-mediated changes in lung development.