Carotid Body Chemoreflex–Dependent Activation Of Epigenetic Mechanisms

Epigenetic regulation by DNA methylation leads to a long‐lasting suppression of gene expression. We recently reported that long‐term (30 days) exposure of rats to intermittent hypoxia (LT‐IH) results in DNA methylation‐dependent suppression of genes encoding anti‐oxidant enzymes (AOEs) in the adrenal medulla, leading to persistent hypertension that does not resolve after the cessation of LT‐IH (Nanduri J. et al . J. Physiol. 2016). LT‐IH–induced DNA methylation was due to increased activity of DNA methyltransferases (Dnmts) resulting from increased Dnmt1 and Dnmt3b protein levels, with no changes in mRNA levels. In the present study, we assessed the mechanisms underlying the induction of increased Dnmt protein levels by LT‐IH. We found that LT‐IH increases the activity of AKT kinases. Treatment of LT‐IH rats with a pan‐AKT inhibitor (GSK690693) prevented the induction of AKT activity and Dnmt protein expression, abolished the suppression of AOE gene expression. LT‐IH‐induced AKT activation required the generation of reactive oxygen species in the adrenal medulla. LT‐IH is sensed by the carotid body, which activates the sympathetic nervous system to stimulate the adrenal medulla. Selective ablation of carotid body inhibited LT‐IH induced oxidative stress, Dnmt activity and DNA hypermethylation of AOE in AM. Overall, our data indicate that LT‐IH induces carotid body chemoreflex‐dependent ROS‐AKT signaling in the adrenal medulla, which triggers epigenetic regulation of AOE genes that alters redox homeostasis leading to persistent elevations of plasma catecholamines and blood pressure. Support or Funding Information (Supported by NIH‐PO1‐HL90554).