Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis

Jayasri Nanduri, Vladislav Makarenko, Vaddi Damodara Reddy, Guoxiang Yuan, Anita Pawar, Ning Wang, Shakil A. Khan, Xin Zhang, Brian Kinsman, Ying Jie Peng, Ganesh K. Kumar, Aaron P. Fox, Lucy A. Godley, Gregg L. Semenza, Nanduri R. Prabhakar

Research output: Contribution to journalArticle

Abstract

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 inmediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.

Original languageEnglish (US)
Pages (from-to)2515-2520
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number7
DOIs
StatePublished - Feb 14 2012

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Keywords

  • Blood pressure
  • Developmental programming
  • Norepinephrine

ASJC Scopus subject areas

  • General

Cite this

Nanduri, J., Makarenko, V., Reddy, V. D., Yuan, G., Pawar, A., Wang, N., Khan, S. A., Zhang, X., Kinsman, B., Peng, Y. J., Kumar, G. K., Fox, A. P., Godley, L. A., Semenza, G. L., & Prabhakar, N. R. (2012). Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 109(7), 2515-2520. https://doi.org/10.1073/pnas.1120600109