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INVITED REVIEW
HIGHLIGHTED TOPICS
Oxygen Sensing in Health and Disease
McKusick-Nathans Institute of Genetic Medicine and Program in Vascular Cell Engineering, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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-1
or HIF-2 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-2 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-1 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-1 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.
hypoxia; pulmonary hypertension; erythropoietin; hypoxia-inducible factor
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