Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

• Published in: The Journal of clinical investigation 1999-03, Vol.103 (5), p.691-696
• Main Authors: Yu, Aimee Y., Shimoda, Larissa A., Iyer, Narayan V., Huso, David L., Sun, Xing, McWilliams, Rita, Beaty, Terri, Sham, James S.K., Wiener, Charles M., Sylvester, J.T., Semenza, Gregg L.
• Format: Article
• Language: English
• ISSN: 0021-9738
• DOI: 10.1172/JCI5912

Chronic hypoxia induces polycythemia, pulmonary hypertension, right ventricular hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1α subunit increases exponentially as O 2 concentration is decreased. Hif1a –/– mouse embryos with complete deficiency of HIF-1α due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death. Hif1a +/– heterozygotes develop normally and are indistinguishable from Hif1a +/+ wild-type littermates when maintained under normoxic conditions. In this study, the physiological responses of Hif1a +/– and Hif1a +/+ mice exposed to 10% O 2 for one to six weeks were analyzed. Hif1a +/– mice demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wild-type littermates. These results indicate that partial HIF-1α deficiency has significant effects on multiple systemic responses to chronic hypoxia. J. Clin. Invest . 103 :691–696 (1999)