O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1.
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.
Semenza
Gregg L
GL
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.
D000818:Animals; D002319:Cardiovascular System / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010100:Oxygen / Q000378:metabolism*; D012137:Respiratory System / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology*
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D010100:Oxygen