Histone Deacetylase 5 Is an Early Epigenetic Regulator of Intermittent Hypoxia Induced Sympathetic Nerve Activation and Blood Pressure.
Histone Deacetylase 5 Is an Early Epigenetic Regulator of Intermittent Hypoxia Induced Sympathetic Nerve Activation and Blood Pressure.
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DOI：
10.3389/fphys.2021.688322
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发表时间：
2021
影响因子：
4
通讯作者：
Nanduri J
中科院分区：
文献类型：
--
作者：
Wang N;Peng YJ;Su X;Prabhakar NR;Nanduri J
间歇性缺氧（IH）是阻塞性睡眠呼吸暂停（OSA）的标志性表现。长期IH（LT-IH）触发氧化还原状态的表观遗传重编程，涉及颈动脉体化学反射途径中的DNA超甲基化，导致持续的交感神经激活和高血压。本研究探讨了IH是否也激活了DNA甲基化以外的表观遗传机制。赖氨酸乙酰化修饰组蛋白是另一个与基因调控相关的主要表观遗传机制。组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）活性之间的平衡决定了赖氨酸乙酰化的水平。在这里，我们报告，暴露于大鼠嗜铬细胞瘤（PC）-12细胞在体外IH表现出降低HDAC酶活性由于蛋白酶体降解HDAC 3和HDAC 5蛋白。机制研究表明，IH诱导的HDAC活性降低增加了缺氧诱导因子（HIF）-1α亚基以及组蛋白（H3）蛋白的赖氨酸乙酰化，导致HIF-1转录活性增加。曲古抑菌素A（TSA），HDAC的抑制剂，模仿IH的作用。对接受10天IH或TSA治疗的大鼠的研究显示，肾上腺髓质（AM）中HDAC活性、HDAC 5蛋白降低，HIF-1依赖性NADPH氧化酶（NOX）-4转录增加，导致血浆儿茶酚胺和血压升高。同样地，血红素加氧酶（HO）-2缺失小鼠，由于自发性呼吸暂停的高发生率（呼吸暂停指数72 ± 1.2呼吸暂停/h）而表现出IH，也表现出AM中HDAC活性和HDAC 5蛋白的降低，沿着升高的循环去甲肾上腺素水平。这些发现表明，组蛋白和非组蛋白的赖氨酸乙酰化是与IH的啮齿动物模型中的交感神经激活和高血压相关的早期表观遗传机制。
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.
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影响因子：
4.7
作者：
Chawla, S;Vanhoutte, P;Bading, H
通讯作者：
Bading, H
DOI：
10.1165/rcmb.2008-0255oc
发表时间：
2009-04-01
影响因子：
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作者：
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影响因子：
64.8
作者：
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Pavletich, NP
DOI：
10.1164/ajrccm.162.6.9904008
发表时间：
2000-12-01
影响因子：
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作者：
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通讯作者：
Young, T