Downregulation of Clock in circulatory system leads to an enhancement of fibrinolysis in mice

Key Laboratory of Chronobiology, Ministry of Health (Sichuan University), Chengdu, Sichuan, PR China.
Experimental Biology and Medicine (Impact Factor: 2.17). 07/2011; 236(9):1078-84. DOI: 10.1258/ebm.2011.010322
Source: PubMed


As a main component of circadian genes, clock plays not only an important role in circadian rhythm but also in the regulation of many physiological systems. The dysfunction of clock genes is associated with the development of various disorders. Many studies have investigated the association between clock genes and blood coagulation and the fibrinolytic system. The present study was designed to investigate the effect of downregulation of circulatory Clock on blood coagulation and fibrinolysis at the initial stage of active phase in male mice. Downregulation of the expression of the Clock gene by siRNA and, subsequently, its effect on the thrombotic potential and the expression of relative coagulative and/or fibrinolytic factors were investigated. It was found that the Clock interfered mice were less liable to thrombosis and showed prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) at Zeitgeber time (ZT) 15. Meanwhile, these mice also showed an increase in factor VII (FVII) and a decrease in thrombomodulin (TM) and plasminogen activator inhibitor 1 (PAI-1) at ZT 15 at both transcriptional and translational levels. PT, APTT and mRNA expressions of fvii, tm and pai-1 were analyzed with the least-squares fit of a 24-h cosine function by single cosinor method; no circadian rhythm was determined in PT and APTT, and a higher amplitude of fvii in the Clock RNAi group was found with a circadian phase shift, while lower amplitudes of tm and pai-1 were found in the Clock RNAi group with nearly no phase shift. All these results suggest that downregulation of the Clock gene in circulatory system has an effect on factors involved in both blood coagulation and fibrinolysis resulting in an enhancement in mice. This may be considered as an indication that Clock regulates thrombotic homeostasis through the fibrinolytic system.

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    ABSTRACT: The exposure to electromagnetic radiation (EMR) would increase the risk of cardiovascular diseases. Central nervous system, especially the suprachiasmatic nucleus in hypothalamus, is a sensitive target of EMR. Clock is a main circadian gene which plays an important role in the circadian system, while factor VII (FVII) plays a central role in the coagulation cascade in the cardiovascular system. To investigate the effect of a continuous EMR exposure on the circadian and cardiovascular systems, we had mature Institute of Cancer Research (ICR) mice exposed to EMR of different power densities. The intake of food and water, the physiological signs, and the motor activity were monitored to have no significant difference. And their expressions of Clock and fvii genes were detected. Our study showed that a series of EMR exposure to ICR mice would have some key gene expression changed without visible changes in physiological signs and activities. We assume that Clock gene could only regulate fvii gene of some specific organ when the exposure to EMR in a certain range of power density.
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