The role of HIF-1 and ROS in cellular and systemic responses to chronic intermittent hypoxia

Sleep-disordered breathing with recurrent apnea is a major cause of morbidity and mortality. Affected individuals have increased risk of systemic hypertension. Sleep apnea results in chronic intermittent hypoxia (CIH). Exposure of rodents to CIH is sufficient to induce hypertension by activating the carotid body reflexes resulting in sympathetic excitation, elevated circulating catecholamines, blood pressure, and ventilation. CIH induces increased levels of reactive oxygen species (ROS) and antioxidant treatment blocks CIH-induced hypertension. The transcriptional activator hypoxia-inducible factor 1 (HIF-1) is induced when mice or cultured cells are subjected to CIH, an effect that is blocked by antioxidants. The carotid bodies from mice heterozygous for a null allele at the locus encoding the HIF-1α subunit appear histologically normal but do not respond to continuous hypoxia or CIH. In contrast to wild-type littermates, when heterozygous-null mice are subjected to CIH they do not develop hypertension or increased levels of HIF-1, catecholamines, or ROS.