Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo

0423812 - BC 2014 RIV DE eng J - Článek v odborném periodiku
Ma, C. - Mizurini, D.M. - Assumpção, T.C.F. - Li, Y. - Qi, Y. - Kotsyfakis, Michalis - Ribeiro, J.M.C. - Monteiro, R.Q. - Francischetti, I.M.B.
Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo.
Thrombosis and Haemostasis. Roč. 122, č. 25 (2013), s. 4094-4106. ISSN 0340-6245. E-ISSN 2567-689X
Grant CEP: GA ČR GAP502/12/2409
Institucionální podpora: RVO:60077344
Klíčová slova: Desmolaris * anticolagulant * vampire bat saliva * FXIa
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 5.760, rok: 2013

The identity of vampire bat saliva anticoagulant remained elusive for almost a century. Sequencing the salivary gland genes from the vampire bat Desmodus rotundus identified Desmolaris as a novel 21.5-kDa naturally deleted (Kunitz 1-domainless) form of tissue factor pathway inhibitor. Recombinant Desmolaris was expressed in HEK293 cells and characterized as a slow, tight, and noncompetitive inhibitor of factor (F) XIa by a mechanism modulated by heparin. Desmolaris also inhibits FXa with lower affinity, independently of protein S. In addition, Desmolaris binds kallikrein and reduces bradykinin generation in plasma activated with kaolin. Truncated and mutated forms of Desmolaris determined that Arg32 in the Kunitz-1 domain is critical for protease inhibition. Moreover, Kunitz-2 and the carboxyl-terminus domains mediate interaction of Desmolaris with heparin and are required for optimal inhibition of FXIa and FXa. Notably, Desmolaris (100 μg/kg) inhibited FeCl3-induced carotid artery thrombus without impairing hemostasis. These results imply that FXIa is the primary in vivo target for Desmolaris at antithrombotic concentrations. Desmolaris also reduces the polyphosphate-induced increase in vascular permeability and collagen- and epinephrine-mediated thromboembolism in mice. Desmolaris emerges as a novel anticoagulant targeting FXIa under conditions in which the coagulation activation, particularly the contact pathway, plays a major pathological role.
Trvalý link: http://hdl.handle.net/11104/0229880