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Epigenetic Regulation of Carotid Body Oxygen Sensing: Clinical Implications
Jayasri Nanduri1, Nanduri R Prabhakar
1Biological Science Division, Institute for Integrative Physiology, 5841 S. Maryland Avenue, MC 5068, Room N-711, University of Chicago, Chicago, IL, 60637, USA, jnanduri@uchicago.edu.
Insights
Apnea of prematurity in infants can lead to adult autonomic dysfunction. Neonatal intermittent hypoxia exposure causes epigenetic changes, specifically DNA methylation, that increase oxidative stress and alter gene expression, contributing to long-term health issues.
Area of Science:
- Physiology
- Epigenetics
- Neonatal Medicine
Background:
- Recurrent apnea with intermittent hypoxia (IH) in preterm infants is a significant clinical issue.
- Adults born preterm show higher rates of sleep-disordered breathing and hypertension, suggesting long-term autonomic dysfunction.
- Neonatal IH exposure in rats leads to augmented carotid body and adrenal chromaffin cell (AMC) responses, irregular breathing, and hypertension in adulthood.
Purpose of the Study:
- To investigate the role of epigenetic mechanisms, particularly DNA methylation, in programming hypoxic sensitivity and autonomic dysfunction following neonatal IH.
- To determine if inhibiting DNA methylation during neonatal IH exposure can prevent long-term autonomic dysfunction.
Main Methods:
- Adult rats exposed to IH during the neonatal period were studied.
- Oxidative stress markers, gene expression (specifically Sod2), DNA methylation patterns, and carotid body/AMC responses were analyzed.
- Neonatal rats were treated with decitabine (a DNA methylation inhibitor) during IH exposure.
Main Results:
- Neonatal IH exposure in rats resulted in increased oxidative stress, decreased anti-oxidant enzyme gene expression (Sod2), and increased pro-oxidant enzyme expression.
- Sod2 gene downregulation was linked to DNA hypermethylation near its transcription start site.
- Decitabine treatment during neonatal IH prevented oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction in adulthood.
Conclusions:
- Epigenetic mechanisms, especially DNA methylation, play a crucial role in the long-term programming of hypoxic sensitivity and autonomic dysfunction initiated by neonatal IH.
- Targeting DNA methylation pathways may offer a therapeutic strategy to prevent adverse long-term health consequences of apnea of prematurity.
Abstract:
Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in infants born preterm. Recent epidemiological studies showed that adults who were born preterm exhibit increased incidence of sleep-disordered breathing and hypertension. Thus, apnea of prematurity predisposes individuals to autonomic dysfunction in adulthood. Experimental studies showed that adult rats exposed to IH as neonates exhibit augmented carotid body and adrenal chromaffin cells (AMC) response to hypoxia and irregular breathing with apneas and hypertension. The enhanced hypoxic sensitivity of the carotid body and AMC in adult rats exposed to neonatal IH was associated with increased oxidative stress, decreased expression of genes encoding anti-oxidant enzymes, and increased expression of pro-oxidant enzymes. Epigenetic mechanisms including DNA methylation leads to long-term changes in gene expression. The decreased expression of the Sod2 gene, which encodes the anti-oxidant enzyme, superoxide dismutase 2, was associated with DNA hypermethylation of a single CpG dinucleotide close to the transcription start site. Treating neonatal rats with decitabine, an inhibitor of DNA methylation, during IH exposure prevented the oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction in adult rats. These findings suggest that epigenetic mechanisms, especially DNA methylation contributes to neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.
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