血压昼夜节律特征及其分子调控机制

正常血压具有典型的昼夜节律特征。血压昼夜节律异常与高血压靶器官损害和心血管事件发生呈明显相关关系,是独立于血压水平的重要致病因素。血压昼夜节律的产生和维持与时钟基因的周期性表达有关。时钟基因bmal1、per2是体内生物钟系统运行的关键基因,其表达水平和节律变化直接调节血压的昼夜节律。     

昼夜节律钟调控代谢的研究进展

生理和行为的昼夜节律性调控对健康生活是必需的。越来越多的流行病学和遗传学证据显示昼夜节律的破坏与代谢紊乱性疾病相关联。在分子水平上,昼夜节律受到时钟蛋白组成的转录一翻译负反馈环的调控。时钟蛋白通过以下两种途径调节代谢：首先,时钟蛋白作为转录因子直接调节一些代谢关键步骤的限速酶和代谢相关核受体的表达,其次作为代谢相关核受体的辅调节因子来激活或抑制其转录活性。虽然时钟蛋白对代谢途径的调节导致代谢物水平呈昼夜节律振荡,但是产生的代谢物反过来又可以影响昼夜节律钟基因的表达,进而影响昼夜节律钟。深入研究昼夜节律钟与代谢的交互调节可能为治疗某些代谢紊乱性疾病提供新的治疗方案。     

果蝇昼夜节律的分子机制研究进展

果蝇由于遗传易操作性而成为一个研究昼夜节律分子机制的理想模式生物 . 到目前为止,通过遗传学和生物化学方法已经鉴定到 10 多个时钟基因 (clock genes) 和许多时钟相关基因,包括时钟输入基因和钟控基因 . 这些时钟基因以及它们的相应产物组成两个互相依赖的转录 / 翻译反馈环路,从而调节行为和生理的昼夜节律 . 果蝇这种核心钟的工作原理同样见于哺乳动物 .     

昼夜节律时钟研究的最新进展

昼夜节律时钟研究的最新进展赵文会（中国科学院国家基因研究中心,上海２００２３３）关键词昼夜节律时钟所有真核生物甚至一些原核生物都有一个基本特性：它们的生化、生理和行为等生命活动过程有昼夜节律性。即使没有外界环境因素刺激,没有任何时间线索,它们的生命活...     

生物钟基因研究进展

昼夜节律是以大约24 h为周期波动的生物现象.这些节律包括血压、体温、激素水平、血中免疫细胞的数量、睡眠觉醒周期循环等.基因水平上的昼夜节律研究还只是刚起步,介绍不同物种控制昼夜行为的共同基因(如period 、timless 、clock基因等)的研究进展,特别是一些有关调控昼夜节律基因的转录因子的研究.同时讨论果蝇和人类生物钟调节的共同分子机制.     

人外周血淋巴细胞核心钟基因Clock和Bmal1的昼夜节律性表达

探讨自然光制下正常成年人外周血淋巴细胞钟基因Clock和Bmal1的昼夜节律性表达。用实时定量RT-PCR方法,测定不同昼夜时点(ZT)受试者外周血淋巴细胞总RNA中核心钟基因Clock和Bmal1的mRNA表达量,通过余弦法和Clock Lab软件获取节律参数,并经振幅检验分析是否存在昼夜节律。结果发现正常成年人外周血淋巴细胞钟基因Clock和Bmal1的mRNA表达呈昼夜节律性振荡(P0.05),Clock的峰时和谷时分别位于ZT13和ZT1,Bmal1的峰时和谷时分别位于ZT12和ZT24;两个基因在所检测的各个昼夜时点中表达水平均有明显差异(P0.05),Bmal1的表达水平较Clock降低;二者表达的峰值相位、振幅、峰时和谷时相一致(P0.05),但Bmal1转录的中值水平以及峰时mRNA水平和谷时mRNA水平降低(P0.05)。提示正常成年人外周血淋巴细胞钟基因Clock和Bmal1的表达存在同步化的昼夜节律性转录特征。     

生物钟基因与肾脏功能和疾病

哺乳动物昼夜节律的产生与生物钟基因的周期性表达密切相关。Bmal1、Clock、Per和Cry是研究最为广泛的核心生物钟基因。肾脏在维持机体体液平衡和血压稳态方面发挥重要作用,其多数生理功能均呈现出一定的昼夜节律性,如动脉血压的调节、肾血流量的维持、肾小球滤过率的调控,以及水的重吸收和钠的排泄等都会随昼夜变化而产生节律性振荡。研究表明,核心生物钟基因的变异与许多肾脏疾病的发生发展密切相关。因此,深入了解核心生物钟基因在肾脏功能和疾病中的作用对防治肾脏疾病具有重要意义。     

生物钟基因3及其表达的调节机制

众所周知 ,生物体的新陈代谢过程 ,细胞和细胞器官的生理功能 ,以及心理行为等生命活动往往随着昼夜循环而发生规律性的变化。就是在实验室恒定的条件下 ,消除一切环境因子的影响 ,生命活动仍表现出昼夜节律性的变化。这说明昼夜节律受体内的测时系统——生物钟的控制。从 5 0年代至今 ,人们对生物的昼夜节律及其调控机制进行了深入地研究 ,特别是应用生物化学和分子生物学的方法 ,使人们逐步了解了生物节律的特点 ,生物钟基因及其表达的调控机制。1　生物钟基因存在于不同生物体中的昼夜节律时钟都表现出 3个共同的特点 :1 )在恒定的环境条…     

ACE2基因多态性与高血压患者血压昼夜节律变化相关性研究

目的:研究血管紧张素转换酶2(ACE2)基因多态性与高血压患者血压昼夜节律变化的关系.方法:选择符合入选标准的高血压患者336例,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法,进行ACE2基因分型.根据血压昼夜节律变化,将高血压患者分为勺型与非勺型两组.分析基因型是否为非勺型血压的危险因素.结果:男性勺型组与非勺型组ACE2基因型多态性的分布存在显著差异,勺型组以G等位基因携带者为主.结论:ACE2基因多态性与男性高血压患者血压昼夜节律相关,携带G等位基因的患者可能更易发生夜间血压升高.     

肾脏生物钟研究概况

越来越多的证据表明生物钟(biological clock)对哺乳动物肾脏功能有重要的调控作用。首先,所有的核心时钟基因(core clock gene)在肾脏中都有表达,而且它们的表达水平表现出显著的近日节律(circadian rhythm);同时,小鼠肾脏相比绝大多数其它组织脏器表达有更多的钟控基因(clock controlled gene,CCG)。另外,肾血流量、肾小球滤过率、肾小管重吸收,以及激素分泌等多种肾脏生理过程呈现出昼夜节律的变化。最后,生物钟紊乱与多种肾脏疾病的进展和预后密切相关。本文将结合最新的一些研究工作从生理和疾病两个角度对肾脏生物钟进行简要综述。     

Altered Orcadian Rhythms of Blood Pressure and Heart Rate in Non-Hemodialysis Chronic Renal Failure

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.     

Altered Orcadian Rhythms of Blood Pressure and Heart Rate in Non-Hemodialysis Chronic Renal Failure

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.     

Rhythmometry gauges treatment of mesor-hypertension in the seventh and eight decades of life

Autorhythmometry of blood pressure by an individual over an age-span of 67 to 72 years showed a strong circadian rhythm superimposed upon significant circaseptan and circannual rhythms. Automatic BP monitoring with an Arteriosonde throughout 24-hour spans on 4 separate occasions, before and during treatment, also indicated a prominent circadian BP rhythm and a treatment-related reduction in circadian mesor. The concept of a blood pressure mesor reference for the antimesor-hypertensive treatment constitutes a valuable guideline in the control of "familial" mesor-hypertension.     

Gradual adjustment of circaseptan-circadian blood pressure and heart rate rhythms after a trans-9-meridian flight.

Circadian and circaseptan adjustment of blood pressure and heart rate after a transmeridian flight by a family of four was relatively fast, but it was not abrupt; it was not completed during the first week in the new setting. Gradual changes continued for the ensuing three weeks. The circadian and circaseptan rhythm characteristics and their adjustment in particular differed among variables in the husband: the circadian component of heart rate adjusted more rapidly than that of blood pressure. The adjustment also differed among two members of the family. A new phenomenon, namely a difference in circadian rhythm adjustment between husband and wife, is also described herein: the wife's circadian rhythm in blood pressure advanced by 9 hours within the 4-week span of recording following a 9-hour advance in living routine (after a 9-zone transmeridian flight); since both schedule and rhythm moved in the same direction (albeit not at the same rate), the behavior may be dubbed concursive. By contrast, the husband delayed to achieve the same adjustment: his behavior was anticursive. The phenomenon of a difference in direction of adjustment for different variables in the same subject has been described earlier as polarity, now qualified as intra-individual polarity, to separate it from the precedent of an intrafamilial or more broadly inter-individual polarity or partitioning, reported apparently for the first time and dubbed 'cursion'.     

Circadian pacemaker function and entrainment during maturation of transgenic hypertensive TGR(mREN2)27 and Sprague-Dawley rats

TGR(mREN2)27 (TGR) transgenic rats develop hypertension due to the mouse mRen-2 gene inserted in their genome. At 5 weeks of age, the blood pressure of TGR rats starts rising, until a maximum is reached at 10 weeks of age. Adult TGR rats show peak values of blood pressure (BP) during the light phase, while heart rate (HR) and motor activity (MA) peak at night. In the present experiment, we evaluated the evolution of circadian rhythms in motor activity, heart rate, and blood pressure of TGR and Sprague-Dawley (SD) rats under 12h light-dark cycles (LD 12:12). Results confirmed that the blood pressure of TGR rats starts to increase at 5 weeks of age, reaching a plateau by the 11th week. Parallel to the increase in blood pressure levels, there was a decrease in the period length of the blood pressure rhythm, a delay in the onset of the alpha phase of the blood pressure rhythm with respect to that of motor activity and heart rate, and a decrease in heart rate levels. In all of the variables studied, the alpha phase of SD rats always started before darkness, whereas that of TGR rats started after lights off. In general, heart rate and motor activity levels of TGR rats were higher than those of SD rats. The amplitude of the circadian rhythms studied was greater in TGR rats than in SD rats. The present results suggest that the different evolution of circadian rhythms in TGR and SD rats might be due to differences in the functioning of the entrainment pathway or the circadian clock itself, which can be detected in young rats and that are probably caused by the expression of the mouse transgene. (Chronobiology International, 18(4), 627-640, 2001)     

Effect of Spaceflight on the Circadian Rhythm,Lifespan and Gene Expression of Drosophila melanogaster

Space travelers are reported to experience circadian rhythm disruption during spaceflight. However, how the space environment affects circadian rhythm is yet to be determined. The major focus of this study was to investigate the effect of spaceflight on the Drosophila circadian clock at both the behavioral and molecular level. We used China’s Shenzhou-9 spaceship to carry Drosophila. After 13 days of spaceflight, behavior tests showed that the flies maintained normal locomotor activity rhythm and sleep pattern. The expression level and rhythm of major clock genes were also unaffected. However, expression profiling showed differentially regulated output genes of the circadian clock system between space flown and control flies, suggesting that spaceflight affected the circadian output pathway. We also investigated other physiological effects of spaceflight such as lipid metabolism and lifespan, and searched genes significantly affected by spaceflight using microarray analysis. These results provide new information on the effects of spaceflight on circadian rhythm, lipid metabolism and lifespan. Furthermore, we showed that studying the effect of spaceflight on gene expression using samples collected at different Zeitgeber time could obtain different results, suggesting the importance of appropriate sampling procedures in studies on the effects of spaceflight.     

基于遥测技术对巴马小型猪部分生理指标的观测

目的：应用遥测技术观察巴马小型猪在清醒自由状态下心电、血压、呼吸、活动等指标昼夜波动变化。方法取雄性6月龄巴马小型猪6只,行浅表股动脉VAP血管通路植入手术,恢复7 d后,用EMAK遥测系统进行24 h连续清醒自由状态下心电、血压、呼吸、活动指标监测,并用EMAK分析软件对上述指标进行分析。结果6月龄巴马小型猪心电、血压、呼吸、活动都有昼夜节律变化,白昼心率显著高于黑夜心率（ P ＜0.01）,且白昼PR间期、QRS间期与QT间期均显著低于黑夜（P ＜0.05,P ＜0.01）,白昼平均心率为76.22次/分,黑夜平均心率为67.03次/分,白昼平均PR间期、QRS间期和QT间期分别为109.97 ms、42.72 ms、380.37 ms,黑夜平均PR间期、QRS间期和QT间期为112.32 ms、44.01 ms、389.24 ms。巴马小型猪白昼收缩压、舒张压、平均压都显著高于夜间（ P ＜0.01）,白昼平均收缩压、舒张压、平均压分别为129.57 mmHg、96.75 mmHg、111.73 mmHg,夜间平均收缩压、舒张压、平均压分别为122.81 mmHg、92.65 mmHg、106.19 mmHg,且黑夜收缩压、舒张压、平均压下降率分别为19.89％、19.05％、19.35％。另外,巴马小型猪在白昼的活动情况与呼吸频率都要显著高于夜间（ P ＜0.01）。结论利用遥测技术可以对清醒自由状态下巴马小型猪心电、血压、呼吸、活动等进行连续监测,能真实的反应小型猪在24 h内上述生理指标的变化规律,为巴马小型猪在药理毒理研究中的应用提供参考。     

Circadian Rhythm of Blood Pressure and Heart Rate in Cardiopathic Patients Before and After Heart Transplantation

The aim of this study was to investigate the natural history of the circadian rhythm of blood pressure (BP) and heart rate (HR) in 10 patients with heart failure (class IV of the New York Heart Association), who underwent heart transplantation because of primary congestive cardiomyopathy. The control group was 10 age-matched clinically healthy subjects. The BP and HR monitor-ings were performed before and after transplantation. Preoperatively, analysis of variance and cosinor methods validated the occurrence of a statistically significant BP and HR circadian rhythm in cardiopathic patients. Over the 4 days after surgery, both the cosinor method and serial section analysis were unable to validate a 24-h periodicity for BP and HR in patients with heart transplants. Six months after surgery, the BP and HR circadian rhythm was not detected as well. One year after transplantation. the BP and HR circadian rhythm was statistically validated. The recovery of the BP and HR circadian rhythm 1 year after heart transplantation can be regarded as a clinical sign of a reacquired susceptibility to neurovegetative chronoregulation.