Objective-Diurnal variations in levels of factor VII (FVII), FVIII, proteins C and S, antithrombin, plasminogen activator inhibitor-1, prothrombin fragment F 1ϩ2 , and D-dimers in healthy humans point to the existence of circadian rhythms of coagulation factors. We sought for temporal fluctuations of tissue factor pathway inhibitor (TFPI) activity in human and mouse plasma. Methods and Results-TFPI activity showed significant daily variations with highest levels in the morning in healthy men (ϩ11%) and in mice at the light-to-dark transition (ϩ63%), the beginning of the physically active period. Variations in FVII activity paralleled those in TFPI. In mice, the feeding schedule had a strong impact on these rhythms. Although restricted feeding and fasting shifted the peak of TFPI, the FVII peak disappeared. Investigation of temporal fluctuations in constant darkness indicated the existence of daily rhythms for TFPI and of true circadian rhythms for FVII. Conclusions-For the first time, we report, both in humans and mice, temporal variations in TFPI activity. The coherent variations in FVII and TFPI activity could interplay to maintain the coagulation equilibrium. The chronobiological patterns should be considered to analyze activity levels of these factors. Moreover, the mouse model could be exploited to investigate modifiers of coagulation rhythms potentially associated to morning peaks of cardiovascular events. Key Words: factor VII Ⅲ TFPI Ⅲ circadian Ⅲ feeding schedule Ⅲ mouse model F requencies of thromboembolic events in humans exhibit marked diurnal variations, 1-3 with peaks from morning to noon. Temporal variations in the occurrence of hemorrhagic events have also been reported. 4 Fluctuations in coagulation factor levels able to influence the hemostatic balance might contribute to these adverse outcomes. Diurnal rhythms in levels of factor VII (FVII), 5 FVIII, 6 proteins C and S 7 , antithrombin, 7 and plasminogen activator inhibitor (PAI)-1 8 have been described in healthy humans. Temporal oscillations in prothrombin fragment F 1ϩ2 5-6 and D-dimer, 6 markers of thrombin generation and fibrinolysis, have been also described. These variations could reflect the existence of circadian rhythms of blood coagulation factors. Circadian rhythms are the overt expression of an internal timing mechanism measuring daily time, with the fundamental adaptive function of providing optimal temporal organization of physiological processes in relation to the environment. 9 Because formal assessment of circadian rhythms in coagulation factor levels is hardly feasible in humans, a circadian control has been so far demonstrated in a mouse model for PAI-1 10 -11 and fibrinogen 12 mRNA expression.Among factors interacting with circadian rhythms, daily availability of food represents a major component. Several studies suggested that postprandial and fasting lipoproteins are associated with plasma levels or activation state of coagulation factors, and particularly of FVII 13-17 that plays a key role in the initiation of the clott...
The mechanisms underlying the circadian control of gene expression in peripheral tissues and influencing many biological pathways are poorly defined. Factor VII (FVII), the protease triggering blood coagulation, represents a valuable model to address this issue in liver since its plasma levels oscillate in a circadian manner and its promoter contains E-boxes, which are putative DNA-binding sites for CLOCK-BMAL1 and NPAS2-BMAL1 heterodimers and hallmarks of circadian regulation. The peaks of FVII mRNA levels in livers of wild-type mice preceded those in plasma, indicating a transcriptional regulation, and were abolished in Clock ؊/؊ ; Npas2 ؊/؊ mice, thus demonstrating a role for CLOCK and NPAS2 circadian transcription factors. The investigation of Npas2؊/؊ and Clock ⌬19/⌬19 mice, which express functionally defective heterodimers, revealed robust rhythms of FVII expression in both animal models, suggesting a redundant role for NPAS2 and CLOCK. The molecular bases of these observations were established through reporter gene assays. FVII transactivation activities of the NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers were (i) comparable (a fourfold increase), (ii) dampened by the negative circadian regulators PER2 and CRY1, and (iii) abolished upon E-box mutagenesis. Our data provide the first evidence in peripheral oscillators for an overlapping role of CLOCK and NPAS2 in the regulation of circadianly controlled genes.Circadian clocks are endogenous oscillators that drive biochemical, physiological, and behavioral processes in organisms (36), and the alteration of which is associated with human diseases (17,26,42). It is well documented that the circadian rhythms of mammals are controlled by a master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus (38) as well as by peripheral oscillators located in most tissues (43).The basic circadian molecular clockworks consist of interacting positive and negative transcriptional/translational feedback loops (11). The positive loop involves CLOCK-BMAL1 and NPAS2-BMAL1 heterodimers, three basic helix-loop-helix transcriptional activators that bind to E-box elements (CA CGTG) located in the regulatory regions of the Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2) genes (3, 13, 16, 24). CRY and PER proteins form oligomers that, once transported into the nucleus, repress their own transcription by inhibiting CLOCK-BMAL1 or NPAS2-BMAL1 (25). Furthermore, other transcription factors (CIPC, DEC1, DEC2, and Fbxl3) play important roles in the negative-feedback loop (15,19,44). The positive and negative limbs are interlaced: CLOCK-BMAL1 heterodimers indirectly regulate a rhythm in Bmal1 transcription; the nuclear orphan receptor genes Reverb␣ and Rora are coordinately activated by CLOCK-BMAL1 to produce proteins that compete for the same promoter element but have opposing actions on Bmal1 transcription (1, 32). Oscillations in gene expression resulting from this feedback loop have period lengths of approximately 24 h, thus giving ri...
The circadian clock, influencing many biological processes, has been demonstrated to modulate levels of specific coagulation factors, but its impact on the coagulation efficiency is unknown. In a mouse model, the authors evaluated the temporal variations in the initial rate of activated factor X (FXa) and thrombin generation. Upon coagulation activation through the FVIIa-TF pathway (extrinsic activation), both parameters showed rhythmic variations with a significant peak at ZT 12, the light-to-dark transition. In mice subjected to a 6-h delayed light-dark cycle, the peak was shifted as expected. These cyclic oscillations were also observed in constant darkness, thus demonstrating, for the first time, the existence of strong circadian rhythms of the initial rate of either FXa or thrombin generation activity levels. These circadian variations overlapped with those that have been recently described in factor VII (FVII) activity. The peak of FXa generation activity was simulated by the addition of purified human FVII, thus indicating that circadian variations in FVII activity are important determinants of the circadian rhythm of the procoagulant cascade efficiency. These findings help to elucidate the complex control on the coagulation process and might contribute in explaining the temporal variations in the frequency of cardiovascular events observed in humans.
It was recently reported that the circadian clock machinery controls plasma levels of factor (F) VII, the serine protease triggering blood coagulation. Here, by exploiting the mouse model, this study showed that variations of photoperiod (i.e., winter or summer conditions or simulated chronic jetlag conditions) have a strong impact on plasma FVII activity levels. Under conditions mimicking summer or winter photoperiods, FVII activity showed a clear 24 h rhythmicity. Interestingly, mean daily FVII activity levels were significantly reduced in mice exposed to summer photoperiods. Behavioral activity rhythms under both photoperiods were synchronized to LD cycles, and the amount of activity per 24 h was comparable. The authors also investigated the influence of chronic jetlag (CJL) on the FVII activity rhythms, which can be easily mimicked in mice through continuous abrupt shifts in the lighting schedule. The exposure of mice to simulated CJL of either consecutive westward or consecutive westward and eastward flights for 15 days did not abolish the behavioral activity rhythms but was associated with a period significantly different from 24 h. Intriguingly, both types of CJL exerted a strong influence on FVII activity rhythms, which were virtually suppressed. Moreover, the mean daily FVII activity was significantly lower in the CJL than in the winter photoperiod condition. Taken together, these findings in mice provide novel insights into the modulation of FVII activity levels, which might have implications for human pathophysiology.
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