Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS
Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS
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DOI：
10.1128/mcb.01332-07
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发表时间：
2008-02-01
影响因子：
5.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Yamashita, Toshiharu;Ohneda, Osamu;Yamamoto, Masayuki
缺氧诱导因子（HIF）在胚胎发育和出生后的生活中对氧稳态至关重要。在这里，我们表明，一种新的HIF家族碱性螺旋-环-螺旋（bHLH）PAS（Per-Arnt-Sim）蛋白，主要在胚胎和新生儿阶段表达，从而指定NEPAS（新生儿和胚胎PAS），作为HIF介导的基因表达的负调节因子。NEPAS mRNA通过选择性剪接从HIF-3 α基因衍生，用抑制性PAS的外显子替换HIF-3 α的第一个外显子。NEPAS可以与Arnt二聚化，并且仅表现出低水平的转录活性，类似于HIF-3a。NEPAS抑制由HIF-1 α和HIF-2 α驱动的报告基因表达。通过产生NEPAS/HIF-3 α基因座靶向破坏的小鼠，我们发现纯合突变小鼠（NEPAS/ HIF-3 α（-/-））是可行的，但显示右心室扩大和肺重塑受损。在NEPAS/HIF-3 α基因敲除小鼠的肺内皮细胞中，内皮素I和血小板衍生生长因子β的表达增加。这些结果证明了一种新的调节机制，其中HIF-1 α和HIF-2 α的活性由内皮细胞中的NEPAS负调节，这与胚胎和新生儿阶段的肺和心脏发育有关。
Hypoxia-inducible factors (HIFs) are crucial for oxygen homeostasis during both embryonic development and postnatal life. Here we show that a novel HIF family basic helix-loop-helix (bHLH) PAS (Per-Arnt-Sim) protein, which is expressed predominantly during embryonic and neonatal stages and thereby designated NEPAS (neonatal and embryonic PAS), acts as a negative regulator of HIF-mediated gene expression. NEPAS mRNA is derived from the HIF-3 alpha gene by alternative splicing, replacing the first exon of HIF-3 alpha with that of inhibitory PAS. NEPAS can dimerize with Arnt and exhibits only low levels of transcriptional activity, similar to that of HIF-3a. NEPAS suppressed reporter gene expression driven by HIF-1 alpha and HIF-2 alpha. By generating mice with a targeted disruption of the NEPAS/HIF-3 alpha locus, we found that homozygous mutant mice (NEPAS/ HIF-3 alpha(-/-)) were viable but displayed enlargement of the right ventricle and impaired lung remodeling. The expression of endothelin I and platelet-derived growth factor beta was increased in the lung endothelial cells of NEPAS/HIF-3 alpha-null mice. These results demonstrate a novel regulatory mechanism in which the activities of HIF-1 alpha and HIF-2 alpha are negatively regulated by NEPAS in endothelial cells, which is pertinent to lung and heart development during the embryonic and neonatal stages.