阻塞性睡眠呼吸暂停(OSA),广泛的呼吸紊乱,导致间歇性缺氧(IH)。OSA患者和IH治疗的啮齿动物表现出增强的交感神经活动和高血压。先前的研究报道缺氧诱导因子-1(HIF-1)对NADPH氧化酶(Nox)的转录激活有助于IH处理的啮齿动物的自主神经功能障碍。赖氨酸乙酰化,由赖氨酸乙酰转移酶(KATs)和赖氨酸脱乙酰酶(KDACs)调节,激活基因转录并在多个生理和病理过程中发挥重要作用。本研究检验了HIF-1α乙酰化的假设,通过p300/CBP(KAT)激活Nox转录,导致交感神经激活和高血压。在嗜铬细胞瘤(PC)-12细胞和用IH处理的大鼠上进行实验。IH增加了KAT活性,p300/CBP蛋白,HIF-1α赖氨酸乙酰化,PC12细胞中HIF-1转录和与Nox4基因启动子结合,这些反应被CTK7A阻断,选择性p300/CBP抑制剂。在IH处理的大鼠中,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蛋白升高有关,HIF-1α稳定,Nox2和Nox4基因和活性氧(ROS)的转录激活,并且所有这些应答在CTK7A处理的IH大鼠中不存在。这些发现表明,p300/CBP对HIF-1α的赖氨酸乙酰化是IH引起的交感神经兴奋和高血压的重要原因。
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 the Nox4 gene 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 of Nox2 and Nox4 genes, 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.