Temporal Variations of Coagulation Factor VII Activity in Mice Are Influenced by Lighting Regime

Colognesi, Ilaria; Pasquali, Vittorio; Foà, Augusto; Renzi, Paolo; Bernardi, Francesco; Bertolucci, Cristiano; Pinotti, Mirko

doi:10.1080/07420520701282307

Cited by 15 publications

(11 citation statements)

References 32 publications

(35 reference statements)

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“…Whether this compensatory mechanism controls the gene expression in cells of peripheral oscillators is strongly debated (8,9), particularly for circadian gene outputs. To address this issue, we took advantage of the key protease synthesized by hepatocytes that triggers blood coagulation (33), factor VII (FVII), whose levels in plasma oscillate in a circadian manner (6,31). Through studies with transgenic mice and cellular and molecular models, we investigated the role of cardinal clock components in circadian transcription in liver oscillators.…”

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confidence: 99%

Evidence for an Overlapping Role of CLOCK and NPAS2 Transcription Factors in Liver Circadian Oscillators

Bertolucci

Cavallari

Colognesi

et al. 2008

Molecular and Cellular Biology

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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...

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confidence: 99%

Evidence for an Overlapping Role of CLOCK and NPAS2 Transcription Factors in Liver Circadian Oscillators

Bertolucci

Cavallari

Colognesi

et al. 2008

Molecular and Cellular Biology

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“…It is uncertain why such an effect on rat fibrinogen concentration was not reported. However, because this effect varies with the dosing time, it is possible that the fibrinogen-lowering effect of raloxifene was not detected in previous experiments because of the dosing times selected for study and perhaps the time of year when the studies were conducted, based on findings of animal research of blood coagulation and human morbid and moral events dependent, at least in part, on rhythms in blood coagulation and underlying mechanisms (Colognesi et al, 2007;Gallerani et al, 2007;Haus, 2007;Manfredini et al, 2005Manfredini et al, , 2007.…”

Section: Discussionmentioning

confidence: 77%

Dosing Time‐Dependent Effect of Raloxifene on Plasma Fibrinogen Concentration in Ovariectomized Rats

Tsuruoka

Hasegawa

Kaneda

et al. 2008

Chronobiology International

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The chronopharmacological effect of raloxifene, a selective estrogen-receptor modulator, was evaluated by repeated dosing of ovariectomized rats. Bilateral ovariectomy or sham operation was performed at age 12 wks, and animals were kept in rooms with a 12 h light-12 h dark cycle. Raloxifene (3 mg/kg, once daily for 10 wks) or vehicle was given repeatedly at either 2 h after lights-on (2 HALO) or 14 h after lights-on (14 HALO). Plasma fibrinogen concentration at the end of the study was reduced by the drug, and the reduction was significantly prominent in rats in whom the drug was dosed at 2 HALO rather than 14 HALO. Femur bone density decreased, and urinary excretion of deoxypyridinoline, an index of bone resorption capacity of osteoclasts, increased in ovariectomized animals at the end of the study. Treatment with raloxifene ameliorated these changes in a dosing time-independent manner. Serum calcium, ALT, and total protein concentrations at the end of the study also did not differ according to treatment regime, which indicates that protein synthesis and liver function may not contribute to the effects. This is the first study to determine dosing time-dependent changes in the efficacy of raloxifene in an animal model of osteoporosis. Because fibrinogen concentration is reported to be a marker of cardiovascular events, consideration of dosing time of raloxifene may be important to obtain a better cardioprotective effect of this medication when it is prescribed to postmenopausal women with osteoporosis.

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“…[18][19][20][21] Since sleep and wake cycles and the circadian system closely interact with each other, we investigated whether partial sleep deprivation has any effect on the thrombin generation activity in plasma, a parameter defining the coagulation cascade efficiency. 22 To this purpose, we exploited the mouse model and a recently developed PSD protocol.…”

Section: Resultsmentioning

confidence: 99%

Chronic sleep deprivation markedly reduces coagulation factor VII expression

Pinotti¹,

Bertolucci²,

Frigato³

et al. 2010

Haematologica

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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.

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Temporal Variations of Coagulation Factor VII Activity in Mice Are Influenced by Lighting Regime

Cited by 15 publications

References 32 publications

Evidence for an Overlapping Role of CLOCK and NPAS2 Transcription Factors in Liver Circadian Oscillators

Evidence for an Overlapping Role of CLOCK and NPAS2 Transcription Factors in Liver Circadian Oscillators

Dosing Time‐Dependent Effect of Raloxifene on Plasma Fibrinogen Concentration in Ovariectomized Rats

Chronic sleep deprivation markedly reduces coagulation factor VII expression

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