Plasma kallikrein enhances platelet aggregation response by subthreshold doses of ADP

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...

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Published in:Biochimie 2017-04, Vol.135, p.72-81
Main Authors: Ottaiano, Tatiana F., Andrade, Sheila S., de Oliveira, Cleide, Silva, Mariana C.C., Buri, Marcus V., Juliano, Maria A., Girão, Manoel J.B.C., Sampaio, Misako U., Schmaier, Alvin H., Wlodawer, Alexander, Maffei, Francisco H.A., Oliva, Maria Luiza V.
Format: Article
Language:English
Subjects:
Adenosine Diphosphate - pharmacology
ADP
Humans
Integrin alphaIIbbeta3
Phosphorylation - drug effects
Plasma kallikrein
Plasma Kallikrein - pharmacology
Platelet aggregation
Platelet Aggregation - drug effects
Platelet Glycoprotein GPIIb-IIIa Complex - metabolism
Receptor, PAR-1 - metabolism
Signal Transduction - drug effects
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Summary: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 αIIbβ3 through interactions with the KGD/KGE sequence motif in huPK. Integrin αIIbβ3 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, AktS473, ERK1/2, and p38 MAPK, and to Ca2+ release. The effect of huPK is blocked by specific antagonists of PAR-1 (SCH 19197) and αIIbβ3 (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. •Plasma kallikrein potentiates platelet responses to subthreshold doses of ADP.•HuPK primes platelet activation to ADP via PAR-1 and integrin activation.•HuPK promotes Src, Akt, ERK, and p38 MAPK phosphorylation in platelets.
ISSN:0300-9084
1638-6183
DOI:10.1016/j.biochi.2017.01.010