Beatrice Saposnik

Unité Inserm U1077, Caen, Lower Normandy, France

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Publications (6)25.56 Total impact

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    ABSTRACT: The endothelial protein C receptor (EPCR) plays a crucial role in the anticoagulant and anti-inflammatory effects of the protein C pathway, whereas its soluble form (sEPCR) exhibits opposite properties. High plasma levels of sEPCR have been observed in subjects carrying the A3 haplotype of PROCR, the EPCR gene. Elevated plasma levels of sEPCR were also recently reported in women with preeclampsia (PE), a multisystemic syndrome involving inflammation, endothelial dysfunction and thrombosis. To determine whether this increase is genetically mediated or acquired, we analyzed sEPCR levels and the A3 haplotype distribution in 145 preeclamptic women and 145 age- and term-matched women with normal pregnancies enrolled in a case-control study. Plasma sEPCR levels were higher in the women with PE than in the controls, and this difference was not due to A3 haplotype over-representation. We observed a positive correlation between sEPCR levels and two markers of endothelium activation/damage (von Willebrand factor and soluble thrombomodulin), and a trend towards a third (sVCAM1). We also found an association between sEPCR levels in the highest quartile and the PE risk. The modest increase of sEPCR levels, together with the correlation with other endothelium activation/damage markers, suggest that it is more an innocent bystander of the endothelium activation/damage than an actor in PE.
    Thrombosis Research 08/2011; 129(2):152-7. · 2.43 Impact Factor
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    ABSTRACT: The endothelial cell protein C receptor also exists in soluble form in plasma (sEPCR), resulting from ADAM17 cleavage. Elevated sEPCR levels are observed in subjects carrying the A3 haplotype, which is characterized by a Ser219Gly substitution in the transmembrane domain, rendering the receptor more sensitive to cleavage. Because sEPCR production is not completely blocked by metalloprotease inhibition, we looked for another mechanism. Comparing mRNA expression patterns and levels in A3 and non-A3 cells from 32 human umbilical cord veins, we detected a truncated mRNA in addition to the full-length mRNA. This truncated mRNA was 16 times more abundant in A3 human umbilical vein endothelial cells than in non-A3 human umbilical vein endothelial cells and encoded a protein lacking the transmembrane domain. We stably expressed a recombinant form of this protein (rEPCRisoform) and a protein mimicking the plasma sEPCR (rEPCRsol). Functional studies of the purified recombinant proteins revealed that the rEPCRisoform bound to recombinant protein C with similar affinity than rEPCRsol and that it also inhibited the anticoagulant activity of APC. Trace amounts of the EPCR isoform were found in the plasma of A3 subjects. These results suggest that the sEPCRisoform could contribute to the regulatory effect of sEPCR in plasma.
    Blood 05/2008; 111(7):3442-51. · 9.78 Impact Factor
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    ABSTRACT: The endothelial cell protein C (PC) receptor (EPCR) facilitates PC activation by the thrombin-thrombomodulin complex. A soluble form of this receptor (sEPCR) found in plasma inhibits both activated PC (aPC) activity and PC activation by competing for PC with membrane-associated EPCR. Elevated sEPCR levels are found in approximately 20% of healthy subjects, but the mechanisms underlying this interindividual variability are unknown. We measured sEPCR levels in 100 healthy male volunteers, and observed 2 phenotypic groups of subjects. The temporal stability of sEPCR levels suggested genetic control. Extensive analysis of the EPCR gene in these subjects revealed 13 polymorphisms in complete linkage disequilibrium; these defined 3 haplotypes, 1 of which (A3) was strongly associated with high sEPCR levels. The high constitutive sEPCR levels observed in A3 haplotype carriers might reduce the efficiency of the PC system and predispose these subjects to venous thrombosis. By studying 338 patients with venous thrombosis and 338 age- and sex-matched healthy subjects, we found that the A3 haplotype was overrepresented in the patients. In multivariate analysis, subjects carrying the A3 haplotype had an increased risk of thrombosis (odds ratio [OR] = 1.8; P =.004). Thus, the A3 haplotype, which is associated with elevated plasma sEPCR levels, is a candidate risk factor for venous thrombosis.
    Blood 03/2004; 103(4):1311-8. · 9.78 Impact Factor
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    ABSTRACT: Protein S (PS) possesses a sex-hormone-binding globulin (SHBG)-like domain in place of the serine-protease domain found in other vitamin K-dependent plasma proteins. This SHBG-like domain is able to bind a complement fraction, C4b-binding protein (C4b-BP). To establish whether the PS SHBG-like domain can fold normally in the absence of other domains, and to obtain information on the specific functions of this region, we expressed the PS SHBG-like domain alone or together with its adjacent domain EGF4. The folding of the two recombinant modules was studied by analyzing their binding to C4b-BP. The apparent dissociation constants of this interaction indicated that both recombinant modules adopted the conformation of native PS, indicating that the PS SHBG-like region is an independent folding unit. We also obtained the first direct evidence that the SHBG-like domain alone is sufficient to support the interaction with C4b-BP. In addition, both recombinant modules were able to bind Ca2+ directly, as shown by the migration shift in agarose gel electrophoresis in the presence of Ca2+, together with the results of equilibrium dialysis and the functional effect of Ca2+ on the C4b-BP/PS interaction, confirming the presence of one Ca2+ binding site within the SHBG-like domain. Neither recombinant module exhibited activated protein C (aPC) cofactor activity in a clotting assay, suggesting that the PS SHBG-like region must be part of the intact molecule for it to contribute to aPC cofactor activity, possibly by constraining the different domains in a conformation that permits optimal interaction with aPC.
    European Journal of Biochemistry 03/2003; 270(3):545-55. · 3.58 Impact Factor