Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis.
Recurrent apnea with intermittent hypoxia is a major clinical problem in preterm infants. Recent studies, although limited, showed that adults who were born preterm exhibit increased incidence of sleep-disordered breathing and hypertension, suggesting that apnea of prematurity predisposes to autonomic dysfunction in adulthood. Here, we demonstrate that adult rats that were exposed to intermittent hypoxia as neonates exhibit exaggerated responses to hypoxia by the carotid body and adrenal chromaffin cells, which regulate cardio-respiratory function, resulting in irregular breathing with apneas and hypertension. The enhanced hypoxic sensitivity was associated with elevated oxidative stress, decreased expression of genes encoding antioxidant enzymes, and increased expression of pro-oxidant enzymes. Decreased expression of the Sod2 gene, which encodes the antioxidant 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 intermittent hypoxia exposure prevented oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction. These findings implicate a hitherto uncharacterized role for DNA methylation in mediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.
Institute 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
Jayasri
J
Nanduri
Vladislav
V
Makarenko
Vaddi Damodara
VD
Reddy
Guoxiang
G
Yuan
Anita
A
Pawar
Ning
N
Wang
Shakil A
SA
Khan
Xin
X
Zhang
Brian
B
Kinsman
Ying-Jie
YJ
Peng
Ganesh K
GK
Kumar
Aaron P
AP
Fox
Lucy A
LA
Godley
Gregg L
GL
Semenza
Nanduri R
NR
Prabhakar
D000818:Animals; D000831:Animals, Newborn; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006321:Heart / Q000502:physiology*; D006706:Homeostasis; D000860:Hypoxia / Q000503:physiopathology*; D008168:Lung / Q000502:physiology*; D051381:Rats