ABSENCE OF CAROTID BODY RESPONSES TO CHRONIC INTERMITTENT HYPOXIA IN MICE DEFICIENT IN HIF‐1á: Implications in cardio‐respiratory responses.

HIF‐1 (hypoxia‐inducible factor‐1) is a key transcription factor that regulates several hypoxia‐inducible genes. Using a cell‐culture model, we recently reported that IH is a potent activator of HIF‐1‐mediated transcription ( Yuan et al. J. Biol. Chem. 2005 ). In the present study we examined the functional significance of HIF‐1 activation by CIH. Experiments were performed on mice that were either wild type (Wt) or heterozygousfor a loss‐of‐function (knockout) allele at the Hif1a locus, whichencodes the O 2 ‐regulated HIF‐1 subunit. Ten day exposure to CIH resulted in robust up‐regulation of HIF‐1 protein in the central nervous system of Wt but not in mutant mice. In Wt mice, CIH increased hypoxic sensitivity of the carotid bodies, and induced sensory long‐term facilitation (LTF). In sharp contrast, in Hif1a +/− mice, CIH neither augmented the hypoxic sensitivity nor induced sensory LTF. Wt mice exposed to CIH exhibited elevated blood pressures, increased plasma norepineprine, and enhanced ventilatory responses to acute hypoxia. In mutant mice, cardio‐respiratory responses to CIH were either absent or markedly attenuated. These results demonstrate that HIF‐1 plays a critical role in eliciting CIH‐induced cardio‐respiratory changes in part due to its effects on hypoxic sensing of the carotid body. Supported by NIH‐HL‐25830, and HL‐55338).