Expression of hypoxia inducible factor 1 in heart

低氧诱导因子1(HIF-1)在有核哺乳动物细胞中表达，以响应氧气供应的减少。HIF-1是一种由HIF-1α和HIF-1β亚基组成的基本螺旋-环PAS转录因子。HIF-1α的表达受细胞内O2浓度的定量调节，决定了HIF-1的生物学活性。低氧感知和信号转导导致HIF-1α表达增加的分子机制尚不清楚。HIF-1激活编码蛋白的基因转录，这些蛋白可分为几类：(I)那些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那些基因，如葡萄糖转运蛋白和糖酵解酶；和(Iii)其他生长/存活因子，如胰岛素样生长因子2。HIF-1已被证明在胚胎发育过程中循环系统的发育以及随后的出生后和成年生活中的生理调节中发挥关键作用。这些研究是基于HIF-1在心肌细胞对缺氧/缺血的反应中发挥重要作用的假设。例如，HIF-1在激活血管内皮生长因子的表达和促进心肌血管生成方面的作用已经得到证实。在本项目中，我们将重点研究三个问题：第一，在心肌细胞中诱导HIF-1活性的机制是什么？第二，诱导后HIF-1的表达对心肌细胞活力有何影响？第二，在存在或不存在预先预适应的情况下，缺血条件下HIF-1的表达对心肌存活有何影响？第三，低氧诱导的哪些基因可能参与预适应的第二窗口，其中哪些基因受HIF-1调控？

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?