Expression of hypoxia inducible factor 1 in heart

心脏缺氧诱导因子1的表达

• 批准号: 6654182
• 负责人: Gregg L Semenza
• 金额: $ 29.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654182
• 关键词: biological signal transduction; cardiac myocytes; cytoprotection; gene expression; gene induction /repression; genetically modified animals; laboratory mouse; laboratory rat; myocardial ischemia /hypoxia; oxygen tension; transcription factor

Hypoxia-inducible factor 1 (HIF-1) is expressed in nucleated mammalian cells in response to reduced O2 availability. HIF-1 is a basic helix-loop helix PAS transcription factor consisting of HIF-1alpha and HIF-1beta subunits HIF-1alpha expression is quantitatively regulated by cellular O2 concentration and determines the biological activity of HIF-1. The molecular mechanisms by which hypoxia is sensed and the signal is transduced leading to increased HIF-1alpha expression are not well understood. HIF-1 activates transcription of genes encoding proteins that can be classified into several groups: (i) those that increase O2 delivery to ells, such as erythropoietin and vascular endothelial growth factor (VEGF), which stimulate erythropoiesis and angiogenesis, respectively, and nitric oxide (NO) synthase-2 and heme oxygenase-1, which synthesize the vasoactive molecules NO and CO, respectively; (ii) those involved in metabolic adaptation to hypoxia such as glucose transporters and glycolytic enzymes; and (iii) other growth/survival factors, such as insulin-like growth factor 2. HIF-1 has been shown to play a critical role in the development of the circulatory system during embryogenesis and its subsequent physiological regulation in postnatal and adult life. The proposed studies are based upon the hypothesis that HIF-1 plays an important role in responses to hypoxia/ischemia by myocardial cells. For example, the role of HIF-1 in activating expression of VEGF and promoting angiogenesis in the myocardium is well established. In this project, we will focus on three questions: First, what are the mechanisms by which HIF-1 activity is induced in myocardial cells? Second, what is the effect of HIF-1 expression of myocardial viability under induced in myocardial cells? Second, what is the effect of HIF-1 expression on myocardial viability under ischemic conditions in the presence or absence of prior precondition? Third, what genes are induced by hypoxia that may contribute to the second window of preconditioning and which of these genes are regulated by HIF-1?

低氧诱导因子1（HIF-1）在有核哺乳动物细胞中表达，以响应减少的O2可用性。HIF-1是由HIF-1 α和HIF-1 β亚基组成的碱性螺旋-环螺旋PAS转录因子。HIF-1 α的表达受细胞内O2浓度的定量调节，并决定HIF-1的生物学活性。缺氧被感知和信号转导导致HIF-1 α表达增加的分子机制尚不清楚。HIF-1激活编码蛋白质的基因的转录，所述蛋白质可分为几组：（i）增加向细胞的O2递送的蛋白质，例如分别刺激红细胞生成和血管生成的红细胞生成素和血管内皮生长因子（VEGF），以及分别合成血管活性分子NO和CO的一氧化氮（NO）合酶-2和血红素加氧酶-1;（ii）参与对缺氧的代谢适应的那些，如葡萄糖转运蛋白和糖酵解酶;和（iii）其它生长/存活因子，如胰岛素样生长因子2。 HIF-1已被证明在胚胎发生期间循环系统的发育及其随后的出生后和成年生活中的生理调节中起关键作用。这些研究基于HIF-1在心肌细胞对缺氧/缺血的反应中起重要作用的假设。例如，HIF-1在心肌中激活VEGF表达和促进血管生成中的作用已得到充分证实。在这个项目中，我们将集中在三个问题：第一，是什么机制，其中HIF-1活性诱导心肌细胞？ 第二，HIF-1的表达对诱导下的心肌细胞存活有何影响？第二，在有或没有预先预处理的缺血条件下，HIF-1表达对心肌存活性的影响是什么？第三，哪些基因被缺氧诱导，可能有助于预适应的第二个窗口，这些基因中哪些受HIF-1的调控？