Coagulazione e Ritmi Circadiani
Recentemente è stato dimostrato come la concentrazione plasmatica di alcuni fattori della coagulazione sia in relazione a ritmi sonno-veglia.
Haematologica. 2010 Aug;95(8):1429-32. Epub 2010 Apr 23.
Chronic sleep deprivation markedly reduces coagulation factor VII expression.
Pinotti M, Bertolucci C, Frigato E, Branchini A, Cavallari N, Baba K, Contreras-Alcantara S, Ehlen JC, Bernardi F, Paul KN, Tosini G.
Neuroscience Institute, Morehouse School of Medicine, 720 Westview Dr, Atlanta, GA 30310, USA.
Abstract
Chronic sleep loss, a common feature of human life in industrialized countries, is associated to cardiovascular disorders. Variations in functional parameters of coagulation might contribute to explain this relationship. By exploiting the mouse model and a specifically designed protocol, we demonstrated that seven days of partial sleep deprivation significantly decreases (-30.5%) the thrombin generation potential in plasma evaluated upon extrinsic (TF/FVIIa pathway) but not intrinsic activation of coagulation. This variation was consistent with a decrease (-49.8%) in the plasma activity levels of factor VII (FVII), the crucial physiologicalal trigger of coagulation, which was even more pronounced at the liver mRNA level (-85.7%). The recovery in normal sleep conditions for three days completely restored thrombin generation and FVII activity in plasma. For the first time, we demonstrate that chronic sleep deprivation on its own reduces, in a reversible manner, the FVII expression levels, thus influencing the TF/FVIIa activation pathway efficiency.
PMID: 20418241 [PubMed - in process]
Mol Cell Biol. 2008 May;28(9):3070-5. Epub 2008 Mar 3.
Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators.
Bertolucci C, Cavallari N, Colognesi I, Aguzzi J, Chen Z, Caruso P, Foá A, Tosini G, Bernardi F, Pinotti M.
Dipartimento di Biochimica e Biologia Molecolare, Università di Ferrara, Via Fossato di Mortara 74, 44100 Ferrara, Italia. pnm@unife.it
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(Delta19/Delta19) 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.
PMID: 18316400 [PubMed - indexed for MEDLINE]
PMCID: PMC2293078
Chronobiol Int. 2007;24(2):305-13.
Temporal variations of coagulation factor VII activity in mice are influenced by lighting regime.
Colognesi I, Pasquali V, Foà A, Renzi P, Bernardi F, Bertolucci C, Pinotti M.
Department of Biology and Evolution and Neuroscience Centre, University of Ferrara, Ferrara, Italy.
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.
PMID: 17453849 [PubMed - indexed for MEDLINE]
Colognesi I, Pasquali V, Foà A, Renzi P, Bernardi F, Bertolucci C, Pinotti M.
Department of Biology and Evolution and Neuroscience Centre, University of Ferrara, Ferrara, Italy.
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.
PMID: 17453849 [PubMed - indexed for MEDLINE]
Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):646-9. Epub 2004 Dec 16.
Daily and circadian rhythms of tissue factor pathway inhibitor and factor VII activity.
Pinotti M, Bertolucci C, Portaluppi F, Colognesi I, Frigato E, Foà A, Bernardi F.
Deparment of di Biochimica e Biologia Molecolare, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italia. pnm@unife.it
OBJECTIVE: Diurnal variations in levels of factor VII (FVII), FVIII, proteins C and S, antithrombin, plasminogen activator inhibitor-1, prothrombin fragment F1+2, 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 (+11%) and in mice at the light-to-dark transition (+63%), 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.
PMID: 15604416 [PubMed - indexed for MEDLINE]
J Biol Rhythms. 2005 Jun;20(3):219-24.
Circadian rhythms in mouse blood coagulation.
Bertolucci C, Pinotti M, Colognesi I, Foà A, Bernardi F, Portaluppi F.
Department of Biology and Neuroscience Centre, University of Ferrara, Ferrara, Italy. bru@unife.it
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.
PMID: 15851528 [PubMed - indexed for MEDLINE]
