Dec1 and CLOCK Regulate Na+/K+-ATPase 1 Subunit Expression and Blood Pressure
Dec1 and CLOCK Regulate Na+/K+-ATPase 1 Subunit Expression and Blood Pressure
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DOI：
10.1161/hypertensionaha.118.11075
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发表时间：
2018-09-01
期刊：
影响因子：
8.3
通讯作者：
Kato, Yukio
中科院分区：
文献类型：
--
作者：
Nakashima, Ayumu;Kawamoto, Takeshi;Kato, Yukio
血压显示昼夜节律，最近的研究表明，参与其控制的分子时钟系统。在生物钟系统中，CLOCK（昼夜运动输出周期终止）：BMAL 1（脑和肌肉芳香烃受体核转位样蛋白-1）异二聚体增强了生物钟基因的启动子活性，而DEC 1（BHLHE 40/STRA 13/SHARP-2）通过竞争与生物钟元件CACGTG E-box结合来抑制CLOCK/BMAL 1增强的启动子活性。然而，该系统调节血压的分子机制仍不清楚。在这里，我们发现DEC 1抑制ATP 1B 1的表达，ATP 1B 1编码Na+/K+-ATP酶的1亚基和血压升高。使用染色质免疫沉淀和染色质免疫沉淀芯片分析，我们发现DEC 1和CLOCK与ATP 1B 1启动子中的E盒结合。荧光素酶分析显示，CLOCK：BMAL 1异二聚体增强从ATP 1B 1启动子的转录，而DEC 1抑制这种反式激活。相应地，Atp 1b 1 mRNA和蛋白质水平在小鼠肾脏，主动脉和心脏显示了昼夜节律，是反相的血压节律。此外，Dec 1缺陷小鼠在这些组织中表现出Atp 1b 1表达增强，血压降低。相反，Clock突变小鼠表现出Atp 1b 1表达减少和血压升高。我们的研究结果提高了DEC 1和CLOCK：BMAL 1对Atp 1b 1的转录调控有助于血压的可能性。
Blood pressure shows a circadian rhythm, and recent studies have suggested the involvement of a molecular clock system in its control. In the clock system, the CLOCK (circadian locomotor output cycles kaput):BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1) heterodimer enhances promoter activity of clock genes, and DEC1 (BHLHE40/STRA13/SHARP-2) represses CLOCK/BMAL1-enhanced promoter activity through competition for binding to the clock element, CACGTG E-box. However, the molecular mechanisms by which this system regulates blood pressure remain unclear. Here, we show that DEC1 suppressed the expression of ATP1B1, which encodes the 1 subunit of the Na+/K+-ATPase and elevated blood pressure. Using chromatin immunoprecipitation and chromatin immunoprecipitation-on-chip analyses, we found that DEC1 and CLOCK bound to E-boxes in the ATP1B1 promoter. Luciferase assays revealed that CLOCK:BMAL1 heterodimer enhanced transcription from the ATP1B1 promoter, whereas DEC1 suppressed this transactivation. Accordingly, Atp1b1 mRNA and protein levels in mouse kidney, aorta, and heart showed a circadian rhythm that was antiphasic to the blood pressure rhythm. Furthermore, Dec1-deficient mice showed enhanced Atp1b1 expression in these tissues and reduced blood pressure. In contrast, Clock-mutant mice showed reduced Atp1b1 expression and elevated blood pressure. Our results raise the possibility that transcriptional regulation of Atp1b1 by DEC1 and CLOCK:BMAL1 contributes to blood pressure.