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Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis

Jayasri Nanduri1, Vladislav Makarenko, Vaddi Damodara Reddy

  • 1Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, Department of Medicine University of Chicago, Chicago, IL 60637, USA. nanduri@uchicago.edu

Proceedings of the National Academy of Sciences of the United States of America
|January 11, 2012
PubMed

Insights

Neonatal intermittent hypoxia exposure in rats programs adult autonomic dysfunction via DNA methylation. This epigenetic mechanism alters hypoxic sensitivity, leading to breathing issues and hypertension.

Area of Science:

  • Physiology
  • Epigenetics
  • Neonatal Medicine

Background:

  • Recurrent apnea and intermittent hypoxia are significant clinical issues in preterm infants.
  • Adults born preterm show increased sleep-disordered breathing and hypertension, suggesting long-term autonomic dysfunction.
  • Apnea of prematurity may predispose individuals to autonomic dysregulation later in life.

Purpose of the Study:

  • To investigate the long-term effects of neonatal intermittent hypoxia on autonomic function in adult rats.
  • To explore the underlying mechanisms, including oxidative stress and gene expression changes.
  • To determine the role of DNA methylation in programming hypoxic sensitivity and autonomic dysfunction.

Main Methods:

  • Neonatal rats were exposed to intermittent hypoxia.
  • Carotid body and adrenal chromaffin cell responses to hypoxia were assessed in adult offspring.
  • Oxidative stress markers, gene expression (including Sod2), and DNA methylation patterns were analyzed.
  • Decitabine, a DNA methylation inhibitor, was administered during neonatal exposure.

Main Results:

  • Neonatal intermittent hypoxia exposure led to exaggerated hypoxic sensitivity, irregular breathing, and hypertension in adult rats.
  • Enhanced hypoxic sensitivity was linked to increased oxidative stress and altered expression of antioxidant/pro-oxidant enzymes.
  • Decreased Sod2 gene expression correlated with DNA hypermethylation near its transcription start site.
  • Decitabine treatment prevented these adverse outcomes, mitigating oxidative stress and autonomic dysfunction.

Conclusions:

  • Neonatal intermittent hypoxia can program long-term autonomic dysfunction in adulthood through epigenetic mechanisms involving DNA methylation.
  • DNA methylation of the Sod2 gene appears critical in mediating the persistent effects of early-life intermittent hypoxia.
  • Targeting DNA methylation may offer a therapeutic strategy to prevent or treat autonomic dysfunction resulting from neonatal apnea.

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