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

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Abstract

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 O2 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% O2 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.

Authors

Aimee Y. Yu, Larissa A. Shimoda, Narayan V. Iyer, David L. Huso, Xing Sun, Rita McWilliams, Terri Beaty, James S.K. Sham, Charles M. Wiener, J.T. Sylvester, Gregg L. Semenza