Intermittent hypoxia (IH) is a hallmark manifestation of Obstructive Sleep Apnea (OSA). Rodents treated with IH exhibit hypertension. Hypoxia-inducible factor (HIF)-1-dependent transcriptional activation of NADPH oxidases (Nox) and the resulting increase in reactive oxygen species (ROS) levels is a major molecular mechanism underlying IH/OSA-induced hypertension. Jumanji C (JmjC)-containing histone lysine demethylases (JmjC-KDMs) are coactivators of HIF-1-dependent transcriptional activation. In the present study, we tested the hypothesis that JmjC-KDMs are required for IH-evoked HIF-1 transcriptional activation of Nox4 and the ensuing hypertension. Studies were performed on pheochromocytoma (PC)12 cells and rats. IH increased KDM6B protein and enzyme activity in PC12 cells in a HIF-1-independent manner as evidenced by unaltered KDM6B activation by IH in HIF-1α shRNA treated cells. Cells treated with IH showed increased HIF-1-dependent Nox4 transcription as indicated by increased HIF-1α binding to hypoxia responsive element (HRE) sequence of the Nox4 gene promoter demonstrated by chromatin immunoprecipitation (ChiP) assay. Pharmacological blockade of KDM6B with GSKJ4, a specific KDM6 inhibitor, or genetic silencing of KDM6B with shRNA abolished IH-induced Nox4 transcriptional activation by blocking HIF-1α binding to the promoter of the NOX4 gene. Treating IH exposed rats with GSKJ4 showed: a) absence of KDM6B activation and HIF-1-dependent Nox4 transcription in the adrenal medullae, as well as b) absence of elevated plasma catecholamines and hypertension. Collectively, these findings indicate that KDM6B functions as a coactivator of HIF-1-mediated Nox4 transactivation and demonstrate a hitherto uncharacterized role for KDM's in IH-induced hypertension by HIF-1.

中文翻译：

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赖氨酸脱甲基酶 KDM6B 调节 HIF-1α 介导的对间歇性缺氧的全身和细胞反应

间歇性缺氧 (IH) 是阻塞性睡眠呼吸暂停 (OSA) 的标志性表现。用 IH 治疗的啮齿动物表现出高血压。NADPH 氧化酶 (Nox) 的缺氧诱导因子 (HIF)-1 依赖性转录激活和由此导致的活性氧 (ROS) 水平增加是 IH/OSA 诱发高血压的主要分子机制。含有 Jumanji C (JmjC) 的组蛋白赖氨酸脱甲基酶 (JmjC-KDM) 是 HIF-1 依赖性转录激活的共激活因子。在本研究中，我们检验了 IH 诱发的 Nox4 的 HIF-1 转录激活和随之而来的高血压需要 JmjC-KDM 的假设。对嗜铬细胞瘤 (PC)12 细胞和大鼠进行了研究。IH 以 HIF-1 非依赖性方式增加 PC12 细胞中的 KDM6B 蛋白和酶活性，HIF-1α shRNA 处理细胞中 IH 未改变的 KDM6B 激活证明了这一点。用 IH 处理的细胞显示 HIF-1 依赖性 Nox4 转录增加，如染色质免疫沉淀 (ChiP) 测定证明的 HIF-1α 与 Nox4 基因启动子缺氧反应元件 (HRE) 序列的结合增加所示。使用 GSKJ4（一种特定的 KDM6 抑制剂）对 KDM6B 进行药理学阻断，或使用 shRNA 对 KDM6B 进行遗传沉默，可通过阻断 HIF-1α 与 NOX4 基因启动子的结合来消除 IH 诱导的 Nox4 转录激活。用 GSKJ4 治疗 IH 暴露的大鼠显示：a) 肾上腺髓质中不存在 KDM6B 激活和 HIF-1 依赖性 Nox4 转录，以及 b) 不存在升高的血浆儿茶酚胺和高血压。