Expression of hypoxia inducible factor 1 in heart

缺氧诱导因子1 （HIF-1）在有核哺乳动物细胞中表达，以响应氧气可用性降低。HIF-1是由HIF-1alpha和HIF-1beta亚基组成的基本螺旋环螺旋PAS转录因子，HIF-1alpha的表达受细胞O2浓度的定量调控，决定HIF-1的生物活性。缺氧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，这些蛋白质可分为几类：(i)增加向细胞输送氧气的基因，如分别刺激红细胞生成和血管生成的促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的一氧化氮合酶-2和血红素加氧酶-1；（ii）参与代谢适应缺氧的蛋白，如葡萄糖转运蛋白和糖酵解酶；（iii）其他生长/生存因子，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在出生后和成年生活中的生理调节中发挥关键作用。提出的研究基于HIF-1在心肌细胞缺氧/缺血反应中起重要作用的假设。例如，HIF-1在激活VEGF表达和促进心肌血管生成中的作用已得到证实。在这个项目中，我们将重点关注三个问题：第一，心肌细胞中诱导HIF-1活性的机制是什么？第二，HIF-1在心肌细胞诱导下对心肌活力的影响是什么？其次，在缺血条件下，HIF-1表达对心肌活力的影响是什么？第三，缺氧诱导的哪些基因可能有助于预处理的第二个窗口，这些基因中哪些受HIF-1调节？

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?