Plasma kallikrein enhances platelet aggregation response by subthreshold doses of ADP

Plasma kallikrein enhances platelet aggregation response by subthreshold doses of ADP

Author Ottaiano, Tatiana F. Autor UNIFESP Google Scholar
Andrade, Sheila S. Autor UNIFESP Google Scholar
de Oliveira, Cleide Autor UNIFESP Google Scholar
Silva, Mariana C. C. Autor UNIFESP Google Scholar
Buri, Marcus V. Autor UNIFESP Google Scholar
Juliano, Maria A. Autor UNIFESP Google Scholar
Girao, Manoel J. B. C. Autor UNIFESP Google Scholar
Sampaio, Misako U. Autor UNIFESP Google Scholar
Schmaier, Alvin H. Google Scholar
Wlodawer, Alexander Google Scholar
Maffei, Francisco H. A. Google Scholar
Oliva, Maria Luiza V. Autor UNIFESP Google Scholar
Abstract Human plasma kallikrein (huPK) potentiates platelet responses to subthreshold doses of ADP, although huPK itself, does not induce platelet aggregation. In the present investigation, we observe that huPK pretreatment of platelets potentiates ADP-induced platelet activation by prior proteolysis of the G-protein -coupled receptor PAR-1. The potentiation of ADP-induced platelet activation by huPK is mediated by the integrin alpha(IIb)beta(3) through interactions with the KGD/KGE sequence motif in huPK. Integrin alpha(IIb)beta(3) is a cofactor for huPK binding to platelets to support PAR-1 hydrolysis that contributes to activation of the ADP signaling pathway. This activation pathway leads to phosphorylation of Src, AktS(473), ERK1/2, and p38 MAPK, and to Cat(2+) release. The effect of huPK is blocked by specific antagonists of PAR-1 (SCH 19197) and alpha(IIb)beta(3) (abciximab) and by synthetic peptides comprising the KGD and KGE sequence motifs of huPK. Further, recombinant plasma kallikrein inhibitor, rBbKI, also blocks this entire mechanism. These results suggest a new function for huPK. Formation of plasma kallikrein lowers the threshold for ADP-induced platelet activation. The present observations are consistent with the notion that plasma kallikrein promotes vascular disease and thrombosis in the intravascular compartment and its inhibition may ameliorate cardiovascular disease and thrombosis. (C) 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.
Keywords ADP
Integrin alphallbbeta3
Plasma kallikrein
Platelet aggregation
xmlui.dri2xhtml.METS-1.0.item-coverage Paris
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES/Drug Discovery)
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
Associacao Beneficente de Coleta de Sangue do Estado de Sao Paulo (COLSAN)
National Cancer Institute, Center for Cancer Research
Grant number FAPESP: 2009/53766-5
FAPESP: 2012/19780-3
CAPES/Drug Discovery: AUXPE 140/2015
CAPES/Drug Discovery: 23038.007776/2014-32
CNPq: 142009/2012-1
Date 2017
Published in Biochimie. Paris, v. 135, p. 72-81, 2017.
ISSN 0300-9084 (Sherpa/Romeo, impact factor)
Publisher Elsevier France-Editions Scientifiques Medicales Elsevier
Extent 72-81
Access rights Closed access
Type Article
Web of Science ID WOS:000397694600009

Show full item record


File Size Format View

There are no files associated with this item.

This item appears in the following Collection(s)




My Account