Tsujino Takeshi, Naito Yoshiro, Kawasaki Daizo, Okuda Satoshi, Sakoda Tsuyoshi, Fujioka Yoshio, Sugaya Takeshi, Ohyanagi Mitsumasa
Department of Internal Medicine, Cardiovascular Division, Hyogo College of Medicine, Nishinomiya, Japan.
Clin Exp Hypertens. 2005 Feb-Apr;27(2-3):159-68.
Both the peripheral biological clock and the renin-angiotensin system regulate mRNA expression of plasminogen activator inhibitor-1 (PAI-1). Our objective was to determine whether angiotensin II (Ang II) type 1 (AT1) receptor-mediated signaling contributes to the development of circadian expression of PAI-1 and clock genes in the heart, aorta, liver, and kidney. We sacrificed AT1a receptor knockout (AT1a-KO) and wild-type (WT) 12 week-old mice every 4 hr. We examined mRNA expression for PAI-1 and clock genes (Per2, Bmal1, and Clock) in heart, aorta, liver, and kidney by using the quantitative reverse transcription-polymerase chain reaction. PAI-1 mRNA showed circadian oscillation with a peak occurring during the light phase in the heart, liver, aorta, and kidney of WT mice. Peak expression of PAI-1 in the liver and aorta was decreased in AT1a-KO mice. On the other hand, cardiac PAI-1 expression in AT1a-KO mice was reduced in the dark phase, during which time its expression level was low. There were no significant differences between WT and AT1a-KO mice in renal PAI-1 expression. Clock genes oscillated synchronously in WT and AT1a-KO mice, and there were no significant differences between the WT and the AT1a-KO mice in their expression. Plasma angiotensin II showed little oscillation in the WT mice. We conclude that AT1a receptor-mediated Ang II signaling modulates the circadian expression of PAI-1 in an organ-specific manner. The effect of the renin-angiotensin system on PAI-1 expression appears to be independent of peripheral clock gene expression.
外周生物钟和肾素-血管紧张素系统均调控纤溶酶原激活物抑制剂-1（PAI-1）的mRNA表达。我们的目的是确定1型血管紧张素II（Ang II）受体介导的信号传导是否有助于心脏、主动脉、肝脏和肾脏中PAI-1和时钟基因昼夜节律表达的发展。我们每4小时处死12周龄的1型血管紧张素II受体a亚型敲除（AT1a-KO）小鼠和野生型（WT）小鼠。我们使用定量逆转录-聚合酶链反应检测心脏、主动脉、肝脏和肾脏中PAI-1和时钟基因（Per2、Bmal1和Clock）的mRNA表达。PAI-1 mRNA在WT小鼠的心脏、肝脏、主动脉和肾脏中呈现昼夜节律振荡，在光照期达到峰值。AT1a-KO小鼠肝脏和主动脉中PAI-1的峰值表达降低。另一方面，AT1a-KO小鼠心脏中PAI-1的表达在黑暗期降低，而黑暗期其表达水平较低。WT小鼠和AT1a-KO小鼠的肾脏PAI-1表达没有显著差异。WT小鼠和AT1a-KO小鼠的时钟基因同步振荡，WT小鼠和AT1a-KO小鼠在时钟基因表达上没有显著差异。WT小鼠血浆血管紧张素II几乎没有振荡。我们得出结论，AT1a受体介导的Ang II信号以器官特异性方式调节PAI-1的昼夜节律表达。肾素-血管紧张素系统对PAI-1表达的影响似乎独立于外周时钟基因表达。
