Epigenetic Regulation of Carotid Body Oxygen Sensing: Clinical Implications

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.

Figure 1

Time course of the hypoxic sensory response of carotid bodies ex vivo from intermittent hypoxia (IH)-exposed and control rat pups reared under normoxia (n = 6 pups in each group; age P5; medium PO₂ = 32− 34 ± 2 Torr). Area between dashed lines indicates duration of hypoxic challenges (modified from Peng et al., 2004).

Figure 2

Effects of intermittent (IH) and sustained hypoxia (SH) on hypoxia–evoked catecholamine (CA) secretion from neonatal adrenal medullary chromaffin cells (AMC). Top panels: examples of hypoxia-evoked CA secretion from AMC derived from postnatal day 5 (P5) rats reared under normoxia (control) or IH or SH. Horizontal black bar represents the duration of the hypoxia (PO₂ ≃ 30 mmHg). Bottom panels: average data on the effects of graded hypoxia on the number of secretory events/min (left) and the average CA molecules released/event (right). PO₂, partial pressure of oxygen (mmHg) in the superfusing medium. Data shown are means ± SE. Control=17 cells, IH=20 cells and SH=18 cells (SH) obtained from 3 different litters in each group. *P < 0.01; **P < 0.001; n.s., not significant (P > 0.05) (modified from Souvannakitti et al., 2009b).