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.
Authors
Nanduri R. Prabhakar, Ying-Jie Peng, Jayasri Nanduri
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.
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ISSN: 0021-9738 (print), 1558-8238 (online)