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Plasma kallikrein enhances platelet aggregation response by subthreshold doses of ADP

  1. Author:
    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.
  2. Author Address

    Univ Fed Sao Paulo, Dept Biochem, Rua Tres Maio 100, BR-04044020 Sao Paulo, Brazil.Univ Fed Sao Paulo, Dept Gynecol, BR-04024002 Sao Paulo, Brazil.Univ Fed Sao Paulo, Dept Biophys, BR-04044020 Sao Paulo, Brazil.Charitable Assoc Blood Collect COLSAN, Sao Paulo, SP, Brazil.Case Western Reserve Univ, Cleveland, OH 44106 USA.Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA.NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA.Univ Estadual Paulista, Dept Orthoped & Surg, Botucatu, SP, Brazil.
    1. Year: 2017
    2. Date: Apr
    3. Epub Date: 2017 Jan 20
  1. Journal: BIOCHIMIE
  2. ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER,
    1. 135
    2. Pages: 72-81
  3. Type of Article: Article
  4. ISSN: 0300-9084
  1. 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.

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External Sources

  1. DOI: 10.1016/j.biochi.2017.01.010
  2. PMID: 28115185
  3. PMCID: PMC5346445
  4. WOS: 000397694600009

Library Notes

  1. Fiscal Year: FY2016-2017
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