P300/CBP Regulates HIF-1-Dependent Sympathetic Activation and Hypertension by Intermittent Hypoxia.
P300/CBP Regulates HIF-1-Dependent Sympathetic Activation and Hypertension by Intermittent Hypoxia.
复制标题
P300/CBP 通过间歇性缺氧调节 HIF-1 依赖性交感神经激活和高血压。
DOI：
10.1165/rcmb.2022-0481oc
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发表时间：
2024
影响因子：
6.4
通讯作者：
Nanduri,Jayasri
中科院分区：
文献类型：
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作者：
Wang,Ning;Su,Xiaoyu;Sams,David;Prabhakar,NanduriR;Nanduri,Jayasri
阻塞性睡眠呼吸暂停（OSA）是一种广泛的呼吸障碍，可导致间歇性缺氧（IH）。患有OSA和IH治疗的啮齿类动物的患者表现出交感神经活动增强和高血压。先前的研究报道了低氧诱导因子-1（HIF-1）对烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（Nox）的转录激活导致IH处理的啮齿动物的自主神经功能障碍。赖氨酸乙酰化受赖氨酸乙酰转移酶（KAT）和赖氨酸去乙酰化酶（KDAC）的调节，激活基因转录，并在多种生理和病理过程中起重要作用。本研究验证了p300/CBP（CREB结合蛋白）（KAT）乙酰化HIF-1α激活Nox转录，导致交感神经激活和高血压的假设。在嗜铬细胞瘤-12细胞和IH处理的大鼠上进行实验。IH可增加KAT活性、p300/CBP蛋白表达、HIF-1α赖氨酸乙酰化、HIF-1转录以及HIF-1与Nox 4基因启动子的结合，这些效应可被选择性p300/CBP抑制剂CTK 7A阻断。IH处理的大鼠血浆去甲肾上腺素（交感神经激活指数）和血压升高。这些反应与p300/CBP蛋白升高、HIF-1α稳定、Nox 2和Nox 4基因转录激活以及活性氧有关，而CTK 7A处理的IH大鼠中不存在所有这些反应。这些结果表明p300/CBP对HIF-1α的赖氨酸乙酰化是IH引起交感神经兴奋和高血压的重要因素。
Obstructive sleep apnea (OSA), a widespread breathing disorder, leads to intermittent hypoxia (IH). Patients with OSA and IH-treated rodents exhibit heightened sympathetic nerve activity and hypertension. Previous studies reported transcriptional activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) by HIF-1 (hypoxia-inducible factor-1) contribute to autonomic dysfunction in IH-treated rodents. Lysine acetylation, regulated by KATs (lysine acetyltransferases) and KDACs (lysine deacetylases), activates gene transcription and plays an important role in several physiological and pathological processes. This study tested the hypothesis that acetylation of HIF-1α by p300/CBP (CREB-binding protein) (KAT) activates Nox transcription, leading to sympathetic activation and hypertension. Experiments were performed on pheochromocytoma-12 cells and rats treated with IH. IH increased KAT activity, p300/CBP protein, HIF-1α lysine acetylation, HIF-1 transcription, and HIF-1 binding to theNox4gene promoter in pheochromocytoma-12 cells, and these responses were blocked by CTK7A, a selective p300/CBP inhibitor. Plasma norepinephrine (index of sympathetic activation) and blood pressures were elevated in IH-treated rats. These responses were associated with elevated p300/CBP protein, HIF-1α stabilization, transcriptional activation ofNox2andNox4genes, and reactive oxygen species, and all these responses were absent in CTK7A-treated IH rats. These findings suggest lysine acetylation of HIF-1α by p300/CBP is an important contributor to sympathetic excitation and hypertension by IH.