HIF-1–Dependent Respiratory, Cardiovascular, and Redox 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 activation of the carotid body and sympathetic nervous system, leading to increased levels of circulating catecholamines. 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) plays an essential role in O2 homeostasis. HIF-1 activity is induced when mice or cultured cells are subjected to CIH, an effect that is blocked by antioxidants. The carotid bodies from mice that are heterozygous for a null (knockout) allele at the locus encoding HIF-1 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. The data suggest the existence of a feed-forward mechanism in which CIH-induced ROS activate HIF-1, which then promotes persistent oxidative stress, which may further amplify HIF-1 activation, with its consequent effects on gene expression.