Neural Regulation of Hypoxia-Inducible Factors and Redox State Drives the Pathogenesis of Hypertension in a Rodent Model of Sleep Apnea

J Appl Physiol (1985). 2015 Nov 15;119(10):1152-6. doi: 10.1152/japplphysiol.00162.2015. Epub 2015 May 7.

Abstract

Obstructive sleep apnea (OSA) is one of the most common causes of hypertension in western societies. OSA causes chronic intermittent hypoxia (CIH) in specialized O2-sensing glomus cells of the carotid body. CIH generates increased reactive oxygen species (ROS) that trigger a feedforward mechanism in which increased intracellular calcium levels ([Ca(2+)]i) trigger increased HIF-1α synthesis and increased HIF-2α degradation. As a result, the normal homeostatic balance between HIF-1α-dependent prooxidant and HIF-2α-dependent antioxidant enzymes is disrupted, leading to further increases in ROS. Carotid body sensory nerves project to the nucleus tractus solitarii, from which the information is relayed via interneurons to the rostral ventrolateral medulla in the brain stem, which sends sympathetic neurons to the adrenal medulla to stimulate the release of epinephrine and norepinephrine, catecholamines that increase blood pressure. At each synapse, neurotransmitters trigger increased [Ca(2+)]i, HIF-1α:HIF-2α, and Nox2:Sod2 activity that generates increased ROS levels. These responses are not observed in other regions of the brain stem that do not receive input from the carotid body or signal to the sympathetic nervous system. Thus sympathetic nervous system homeostasis is dependent on a balance between HIF-1α and HIF-2α, disruption of which results in hypertension in OSA patients.

Keywords: NADPH oxidase; hypoxia-inducible factors; oxidative stress; superoxide dismutase.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carotid Sinus / innervation
  • Carotid Sinus / metabolism
  • Disease Models, Animal*
  • Humans
  • Hypertension / etiology
  • Hypertension / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Mice, Knockout
  • Nerve Net / metabolism
  • Oxidation-Reduction
  • Sensory Receptor Cells / metabolism*
  • Sleep Apnea Syndromes / complications
  • Sleep Apnea Syndromes / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • endothelial PAS domain-containing protein 1