Hypoxia-inducible factors and hypertension: lessons from sleep apnea syndrome

Systemic hypertension is one of the most prevalent cardiovascular diseases. Sleep-disordered breathing (SDB) with recurrent apnea is a major risk factor for developing essential hypertension. Chronic intermittent hypoxia (CIH) is a hallmark manifestation of recurrent apnea. Rodent models patterned after the O2 profiles seen with SDB patients showed that CIH is the major stimulus for causing systemic hypertension. This article reviews the physiological and molecular basis of CIH-induced hypertension. Physiological studies have identified that augmented carotid body chemosensory reflex and the resulting increase in sympathetic nerve activity are major contributors to CIH-induced hypertension. Analysis of molecular mechanisms revealed that CIH activates hypoxia-inducible factor (HIF)-1 and suppresses HIF-2-mediated transcription. Dysregulation of HIF-1- and HIF-2-mediated transcription leads to imbalance of pro-oxidant and anti-oxidant enzyme gene expression resulting in increased reactive oxygen species (ROS) generation in the chemosensory reflex which is central for developing hypertension.