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      O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1.

      1
      Journal of applied physiology (Bethesda, Md. : 1985)
      American Physiological Society

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          Abstract

          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.

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          Author and article information

          Journal
          J Appl Physiol (1985)
          Journal of applied physiology (Bethesda, Md. : 1985)
          American Physiological Society
          8750-7587
          0161-7567
          Mar 2004
          : 96
          : 3
          Affiliations
          [1 ] 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.
          Article
          96/3/1173
          10.1152/japplphysiol.00770.2003
          14766767
          6227c565-68e7-439f-b790-25605497f5e3
          History

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