Hypoxia-inducible factors and obstructive sleep apnea

Abstract

Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This Review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of antioxidant genes by HIF-2. ROS in turn activate chemoreflex and suppress baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We also discuss how increased ROS generation by HIF-1 contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.

Figure 1. Schematic presentation of HIF-dependent signaling pathways in OSA-induced hypertension.

Hypoxia-induced changes in HIF-1α and HIF-2α levels exacerbate increases in ROS levels. Within the carotid body, ROS elevations modify the balance between CO and H₂S (lower left) as well as attenuate the carotid baroreflex (lower right), resulting in increased sympathetic nerve activity that can drive hypertension. Ca²⁺, calcium; CO, carbon monoxide; CSE, cystathionine-γ-lyase; ECE, endothelin-converting enzyme; ET-1, endothelin-1; H₂S, hydrogen sulfide; HO-2, heme oxygenase-2; NOX, NADPH oxidase.

Figure 2. Activation of epigenetic mechanisms involving DNA methylation of antioxidant enzyme genes either in response to long-term IH associated with untreated and undiagnosed OSA or in young adults who had apnea of prematurity in neonatal life.

AOE, antioxidant enzyme; DNMTs, DNA methyltransferases.

Figure 3. Schematic presentation of proposed mechanism(s) for HIF-1–dependent pancreatic β cell dysfunction manifesting as hypersecretion of insulin and insulin resistance and cognitive dysfunction evoked by OSA/IH.

GluN1, glutamate ionotropic receptor NMDA type subunit 1; LTP, long-term potentiation.