Semenza Gregg L
Johns Hopkins University School of Medicine, McKusick-Nathans Institute of Genetic Medicine, Program in Vascular Cell Engineering, Institute for Cell Engineering, Baltimore, MD 21205, USA.
J Appl Physiol (1985). 2004 Mar;96(3):1173-7; discussion 1170-2. doi: 10.1152/japplphysiol.00770.2003.
The cardiovascular and respiratory systems play key roles in O(2) homeostasis. Physiological responses to hypoxia involve changes in gene expression that are mediated by the transcriptional activator hypoxia-inducible factor (HIF)-1. Analysis of mice heterozygous for a knockout allele at the locus encoding the O(2)-regulated HIF-1alpha or HIF-2alpha subunit has revealed that these proteins are required for multiple physiological responses to chronic hypoxia, including erythrocytosis and pulmonary vascular remodeling. In mice with partial HIF-2alpha deficiency, hypoxia-induced expression of endothelin-1 and norepinephrine is dramatically impaired, and the mice fail to develop pulmonary hypertension after 4 wk of exposure to 10% O(2). In mice with partial HIF-1alpha deficiency, the ability of the carotid body to sense and/or respond to acute or chronic hypoxia is lost. In wild-type mice, brief episodes of intermittent hypoxia are sufficient to induce production of erythropoietin (EPO), which protects the heart against apoptosis after ischemia-reperfusion, whereas in mice with partial HIF-1alpha deficiency, intermittent hypoxia does not induce EPO production or cardiac protection. Parenteral administration of EPO to rodents is sufficient to induce dramatic protection against ischemia-reperfusion injury in the heart. Thus HIF-1 mediates critical physiological responses to hypoxia, and the elucidation of these homeostatic mechanisms may lead to novel therapies for the most common causes of mortality in the US population.
心血管系统和呼吸系统在氧气稳态中发挥关键作用。对缺氧的生理反应涉及基因表达的变化，这些变化由转录激活因子缺氧诱导因子（HIF）-1介导。对编码受氧气调节的HIF-1α或HIF-2α亚基的基因座上的敲除等位基因杂合的小鼠进行分析发现，这些蛋白质是对慢性缺氧的多种生理反应所必需的，包括红细胞增多症和肺血管重塑。在部分HIF-2α缺乏的小鼠中，缺氧诱导的内皮素-1和去甲肾上腺素的表达显著受损，并且在暴露于10%氧气4周后，这些小鼠无法发展为肺动脉高压。在部分HIF-1α缺乏的小鼠中，颈动脉体感知和/或应对急性或慢性缺氧的能力丧失。在野生型小鼠中，短暂的间歇性缺氧发作足以诱导促红细胞生成素（EPO）的产生，EPO可保护心脏免受缺血再灌注后的凋亡，而在部分HIF-1α缺乏的小鼠中，间歇性缺氧不会诱导EPO产生或心脏保护作用。对啮齿动物进行促红细胞生成素的肠胃外给药足以诱导对心脏缺血再灌注损伤的显著保护作用。因此，HIF-1介导对缺氧的关键生理反应，阐明这些稳态机制可能会为美国人群中最常见的死亡原因带来新的治疗方法。
