Lysine Deacetylases and Demethylases: Early Epigenetic Regulators of Intermittent Hypoxia induced Sympathetic Activation and Blood Pressure

Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA). Long term IH (LT-IH) triggers epigenetic reprogramming of the redox state involving DNA hypermethylation leading to persistent sympathetic activation and hypertension. Present study examined whether IH also activates epigenetic mechanism(s) other than DNA methylation. Lysine modifications of histones is another major epigenetic mechanism associated with gene regulation. Interplay between lysine deacetylases (HDACs) and demethylases (KDMs) differentially regulate gene expression. Lysine acetylation of histone opens up the chromatin thereby facilitating binding of transcription factors. On the other hand, KDMs regulate transcription by demethylating histone lysines which activate gene expression. Here we report that exposure of rat pheochromocytoma (PC)-12 cells to IH in vitro exhibit reduced HDAC5 and increased KDM6B enzyme activity leading to increased HIF-1α stability and transcriptional activity. Treatment of rats with Trichostatin A (TSA), an inhibitor of HDACs increased HIF-1 dependent NADPH oxidase (NOX)-4 transcription, in adrenal medullae (AM), resulting in elevated plasma catecholamines and blood pressure. Treating IH exposed rats with GSKJ4 an inhibitor of KDMs blocked HIF-1 dependent transcriptional activation of NOX4, as well as absence of elevated plasma catecholamines and hypertension. These findings indicate a hitherto uncharacterized role of HDACs and KDMs as early epigenetic regulators in IH-augmented sympathetic nerve activation and hypertension in rodent models of IH.