Reduced nitric oxide causes age-associated impairment of circadian rhythmicity
Reduced nitric oxide causes age-associated impairment of circadian rhythmicity
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DOI：
10.1161/circresaha.107.162230
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发表时间：
2008-03-14
影响因子：
20.1
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Kunieda, Takeshige;Minamino, Tohru;Komuro, Issei
老年人昼夜节律性受损被认为是导致动脉粥样硬化和高血压等与年龄相关的疾病的原因。内皮源性一氧化氮(NO)是心血管内稳态的重要调节因子，但其产量随着年龄的增长而下降，从而导致血管功能障碍。我们在这里表明，昼夜节律性受损与一氧化氮的产生随着年龄的增长而减少有关。NO供体通过cAMP反应元件依赖的途径和E-box增强子元件依赖的途径显著上调Clock基因期的启动子活性。NO的磷酸化和S亚硝化都参与了这种上调。在老年动物中，内皮一氧化氮合酶活性在白天显著降低，并伴有时钟基因表达的损害和血压的昼夜变化。用NO供体治疗老年动物，显著改善了损伤。抑制NO合成酶活性还会导致Clock基因表达和血压节律的障碍。这些结果表明，NO是心血管系统中昼夜节律的关键调节因子，可能成为治疗年龄相关性昼夜节律改变的新靶点。
Impairment of circadian rhythmicity in the elderly has been suggested to cause age-associated diseases such as atherosclerosis and hypertension. Endothelium-derived nitric oxide (NO) is a critical regulator of cardiovascular homeostasis, but its production declines with aging, thereby inducing vascular dysfunction. We show here that impaired circadian rhythmicity is related to a decrease of NO production with aging. Treatment with an NO donor significantly upregulated the promoter activity of the clock gene Period via the cAMP response element-dependent and the E-box enhancer element-dependent pathways. Both phosphorylation and S-nitrosylation by NO are involved in this upregulation. In aged animals, endothelial NO synthase activity was markedly decreased during the daytime, along with impairment of clock gene expression and the circadian variation in blood pressure. Treatment of aged animals with an NO donor significantly improved the impairments. Inhibition of NO synthase activity also led to impairment of clock gene expression and blood pressure rhythm. These results suggest that NO is a key regulator of the circadian clock in the cardiovascular system and may be a novel target for the treatment of age-associated alteration of circadian rhythms.