Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1
Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1
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DOI：
10.1042/bj20021087
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发表时间：
2003-02-15
影响因子：
4.1
通讯作者：
Park, JW
中科院分区：
文献类型：
--
作者：
Chun, YS;Hyun, JY;Park, JW
心房利钠肽（ANP）是一种心脏肽，其转录在缺血心室中上调。然而，ANP诱导的分子机制尚不清楚。这项研究表明，ANP mRNA在大鼠心肌缺血的早期阶段诱导表达，缺氧诱导因子-1（HIF-1）α表达之前。在H9 c2和新生心肌细胞中，ANP基因也被缺氧或HIF-1诱导剂如CoCl 2和去铁胺诱导。克隆了大鼠ANP基因的2307 bp的5 '侧翼区，并将其与荧光素酶基因融合。启动子活性的证据仅在心肌细胞中明显，并且由缺氧和HIF-1诱导剂诱导。HIF-1 α的过表达显著增强了ANP启动子的活性，而一种显性负性亚型完全抑制了它。一个启动子区，含有HIF-1结合序列，直接受HIF-1调节。另一个区域也被HIF-1激活，尽管没有HIF-1结合序列。这些结果表明，HIF-1增强了缺氧心肌细胞中ANP基因的反式激活，这意味着HIF-1对ANP启动子的刺激实际上可能是缺血心室肌中ANP基因诱导的原因。
Atrial natriuretic peptide (ANP) is a cardiac peptide, the transcription of which is up-regulated in the ischaemic ventricle. However, the molecular mechanism of ANP induction is unclear. This study demonstrated that ANP mRNA expression in rat ventricular myocardium is induced in an early phase of ischaemia, preceded by hypoxia-inducible factor-1 (HIF-1) alpha expression. The ANP gene was also induced by hypoxia or HIF-1 inducers such as CoCl2 and desferrioxamine in H9c2 and neonatal cardiomyocytes. The 2307 bp 5'-flanking region of the rat ANP gene was cloned and fused to the luciferase gene. Evidence of the promoter activity was only apparent in the myocytes and was induced by hypoxia and HIF-1 inducers. The overexpression of HIF-1alpha markedly enhanced ANP promoter activity, and a dominant-negative isoform completely suppressed it. We demonstrated that the promoter regions are essential for hypoxic ANP induction. One promoter region, containing the HIF-1-binding sequence, is regulated directly by HIF-1. The other region is also activated by HIF-1 despite having no HIF-1-binding sequence. These results suggest that HIF-1 enhances the transactivation of the ANP gene in hypoxic myocytes, implying that stimulation of the ANP promoter by HIF-1 may in fact be responsible for the induction of the ANP gene in ischaemic ventricular myocardium.