Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis

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 in mediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.blood pressure | developmental programming | norepinephrine I n preterm infants, respiratory disorders with recurrent apnea and the associated intermittent hypoxemia (IH) are major clinical problems (1). Infants with recurrent apnea exhibit an enhanced hypoxic ventilatory response (2), an effect that was attributed to a heightened chemo-reflex arising from the carotid body, which is a sensory organ that detects changes in arterial blood O 2 levels (3). Carotid body sensitivity to hypoxia is reset after birth and this effect is modulated by chronic hypoxia (4-6). Neonatal rats exposed to IH showed exaggerated carotid body and ventilatory responses to hypoxia (7,8). Catecholamine secretion from the adrenal medulla is another important homeostatic mechanism that preserves cardiovascular function under hypoxia (9, 10). In neonates, hypoxia facilitates catecholamine secretion by directly affecting the excitability of adrenal chromaffin cells (11), a response that is markedly augmented in neonatal rats subjected to IH (12,13). Exaggerated hypoxic sensing of carotid body and adrenal chromaffin cells in neonates by IH is attributed to increased oxidative stress (12,14). IH also augments hypoxic responses of the carotid body and adrenal medulla in adult rats (15, 16), which is completely reversed following reoxygenation (15). In striking contrast, in neonates the augmented hypoxic sensitivity that is induced by IH persists into adulthood (8,12,14). The molecular mechanisms underlying the long-lasting effects of neonatal IH on hypoxic sensing and its physiological consequences in adult life are not known.It is being increasingly recognized that environm...

Prenatal Hypoxia Reduces Mitochondrial Protein Levels and Cytochrome c Oxidase Activity in Offspring Guinea Pig Hearts

“…These include epigenetic mechanisms of DNA methylation 62 and histone deacetylation as well as posttranslational modification. DNA methylation has been reported to be increased in response to both prenatal HPX in heart ventricles 63 and oxidative stress of cancer cells, 64 carotid body, 65,66 and the heart. 67 We have previously shown that prenatal HPX increases HIF-1a protein levels in HPX-exposed fetal hearts, 6 indicating local tissue HPX.…”

Mechanisms of Superoxide Signaling in Epigenetic Processes: Relation to Aging and Cancer

“…Superoxide overproduction decreased the expression of Sod2 gene due to DNA hypermethylation of a single CpG dinucleotide close to the transcription site in adult rats with apneas [91]. After nickel exposure, the enhanced superoxide formation resulted in histone hypoacetylation in human leukemia cells [92].…”

A potential role of hydrogen sulfide (H2S) in the regulation of the Ras-ERK signaling-dependent transcription of DNA methyltransferases

“…For example, in vivo study demonstrates DNMT1, DNMT3b, but not DNMT3a upregulation and subsequent DNA hypermathylation as a result of neonatal hypoxia [44]. S.O.…”