Titre
Unexpected Role for Connexin37 in Circulating FVIII and Coagulation
Type
abstract de conférence/colloque
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Série
Circulation
Auteur(s)
Burnier, Laurent
Auteure/Auteur
Pfenniger, Anna
Auteure/Auteur
Taffet, Steven
Auteure/Auteur
Delmar, Mario
Auteure/Auteur
Fontana, Pierre
Auteure/Auteur
Angelillo-Scherrer, Anne
Auteure/Auteur
Kwak Brenda, R.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
Titre du livre ou conférence/colloque
82nd Scientific Session of the American Heart Association
Adresse
Orlando, Florida, November 14-18, 2009
ISBN
0009-7322
Statut éditorial
Publié
Date de publication
2009
Volume
120
Première page
1099
Peer-reviewed
Oui
Langue
anglais
Notes
Meeting Abstract
Résumé
The gap junction protein connexin37 (Cx37) plays an important role in cell-cell communication in the vasculature. Cx37 is expressed in endothelial cells, platelets and megakaryocytes. We have recently shown that Cx37 limits thrombus propensity by permitting intercellular signaling between aggregating platelets. Here, we have performed high throughput phage display to identify potential binding partners for the regulatory intracellular C-terminus of Cx37 (Cx37CT). We retrieved 2 consensus binding motifs for Cx37CT: WHK...[K,R]XP... and FH-K...[K,R]XXP.... Sequence alignment against the NCBI protein database indicated 66% homology of one the selected peptides with FVIII B-domain. We performed cross-linking reactions using BS3 and confirmed that an 11-mer peptide of the FVIII B-domain sequence linked to recombinant Cx37CT. In vitro binding of this peptide to Cx37CT was also confirmed by surface plasmon resonance. The dissociation constant of FVIII B-domain peptides to Cx37CT was ~20 uM. Other peptide sequences, designed upstream or downstream of the FVIII B-domain sequence, showed very low or no affinity for Cx37CT. Finally, in vivo studies revealed that thrombin generation in platelet-poor plasma from Cx37-/- mice (endogenous thrombin potential: 634±11 nM min, mean±SEM) was increased compared to Cx37+/+ mice (427±12, P<0.001). Moreover, partial activated thromboplastin time (aPTT) was shorter in Cx37-/- (39.7±1.5 s) than in Cx37+/+ mice (45.9±1.8, P=0.03), whereas prothrombin time was comparable. The shorter aPTT in Cx37-/- mice correlated with higher circulating FVIII activity (46.0±0.7 vs. 53.5±2.7 s for Cx37+/+, P=0.03). Overall, our data show for the first time a functional interaction between FVIII and Cx37. This interaction may be relevant for the control of FVIII secretion and, thereby, in the regulation of levels of FVIII circulating in blood. In addition, these results may open new perspectives to improve the efficiency of recombinant FVIII manufacturing.
PID Serval
serval:BIB_CD61B863786C
Date de création
2010-02-24T10:54:57.606Z
Date de création dans IRIS
2025-05-21T04:05:25Z