Histone Deacetylase 5 Is an Early Epigenetic Regulator of Intermittent Hypoxia Induced Sympathetic Nerve Activation and Blood Pressure.

Ning Wang,Xiaoyu Su,Nanduri R Prabhakar,Ying-Jie Peng,Jayasri Nanduri

doi:10.3389/fphys.2021.688322

Ning Wang, Xiaoyu Su + Show 3 more

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https://doi.org/10.3389/fphys.2021.688322

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Abstract

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 in the carotid body chemo reflex pathway resulting in persistent sympathetic activation and hypertension. Present study examined whether IH also activates epigenetic mechanism(s) other than DNA methylation. Histone modification by lysine acetylation is another major epigenetic mechanism associated with gene regulation. Equilibrium between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) determine the level of lysine acetylation. Here we report that exposure of rat pheochromocytoma (PC)-12 cells to IH in vitro exhibited reduced HDAC enzyme activity due to proteasomal degradation of HDAC3 and HDAC5 proteins. Mechanistic investigations showed that IH-evoked decrease in HDAC activity increases lysine acetylation of α subunit of hypoxia inducible factor (HIF)-1α as well as Histone (H3) protein resulting in increased HIF-1 transcriptional activity. Trichostatin A (TSA), an inhibitor of HDACs, mimicked the effects of IH. Studies on rats treated with 10 days of IH or TSA showed reduced HDAC activity, HDAC5 protein, and increased HIF-1 dependent NADPH oxidase (NOX)-4 transcription in adrenal medullae (AM) resulting in elevated plasma catecholamines and blood pressure. Likewise, heme oxygenase (HO)-2 null mice, which exhibit IH because of high incidence of spontaneous apneas (apnea index 72 ± 1.2 apnea/h), also showed decreased HDAC activity and HDAC5 protein in the AM along with elevated circulating norepinephrine levels. These findings demonstrate that lysine acetylation of histone and non-histone proteins is an early epigenetic mechanism associated with sympathetic nerve activation and hypertension in rodent models of IH.

Highlights

Obstructive sleep apnea (OSA) is a widespread breathing disorder affecting 10–15% of adult population (Peppard et al, 2013)
The enzyme activities of histone deacetylases (HDACs) and Sirtuins (SIRT) were determined in cells treated with 60 cycles of Intermittent hypoxia (IH) (IH60) or alternating cycles of room air (N) which served as controls
Treating cells with 50 nM Trichostatin A (TSA), which is an inhibitor of HDACs but not SIRTs (Finnin et al, 1999; Bertrand, 2010), mimicked the effects of IH by markedly reducing HDAC activity compared to vehicle treated controls (Figure 1C)

Summary

Introduction

Obstructive sleep apnea (OSA) is a widespread breathing disorder affecting 10–15% of adult population (Peppard et al, 2013). Intermittent hypoxia (IH), a hallmark manifestation of OSA, is a major contributing factor to hypertension (reviewed in Prabhakar et al, 2020). Rats treated with long-term-IH (30 days; LT-IH) exhibit hypertension and heightened sympathetic nerve activity persisting even after a 30-day recovery in room air (Nanduri et al, 2017). The long-lasting blood pressure elevation evoked by LT-IH is reminiscent of treatment-resistant hypertension reported in a subset of OSA patients. LT-IH evoked long-lasting hypertension was due to persistent elevation of ROS caused by epigenetic suppression of anti-oxidant enzyme genes by DNA methylation (Nanduri et al, 2017)

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