Plasma kallikrein enhances platelet aggregation response by subthreshold doses of ADP

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Ottaiano, Tatiana F. ; Andrade, Sheila S. ; de Oliveira, Cleide ; Silva, Mariana C. C. ; Buri, Marcus V. ; Juliano, Maria A. ; Girao, Manoel J. B. C. ; Sampaio, Misako U. ; Schmaier, Alvin H. ; Wlodawer, Alexander ; Maffei, Francisco H. A. ; Oliva, Maria Luiza V.

• Tipo de documento: Artigo Científico
• Fonte: Biochimie; v. 135, p. 72-81, APR 2017.
• Citações Web of Science: 8

Resumo

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. (AU)

• Processo FAPESP: 09/53766-5 - Proteínas de origem vegetal com seletividade para inibição de enzimas de mamíferos e seu papel como agente anti-inflamatório, antitrombótico, antidiabético e antitumoral
• Beneficiário: Maria Luiza Vilela Oliva
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/19780-3 - Cultura heterotípica: efeitos da associação entre células epiteliais, estroma mamário, macrófagos e plaquetas no câncer de mama: liberação de enzimas proteolíticas e sinalização dos receptores toll-like
• Beneficiário: Manoel João Batista Castello Girão
• Linha de fomento: Auxílio à Pesquisa - Regular