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O2-regulated Gene Expression: Transcriptional Control Of Cardiorespiratory Physiology By HIF-1

Gregg L. Semenza

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The cardiovascular and respiratory systems play key roles in O2 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 O2-regulated HIF-1α or HIF-2α 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-2α 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% O2. In mice with partial HIF-1α 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-1α 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.