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Phosphoinositide 3‐kinase inhibition reverses platelet aggregation triggered by the combination of the neutrophil proteinases elastase and cathepsin G without impairing α IIb β 3 integrin activation
Author(s) -
Trumel Cathy,
Si-Tahar Mustapha,
Balloy Viviane,
Chignard Michel,
Chap Hugues,
Payrastre Bernard,
Plantavid Monique,
Pidard Dominique
Publication year - 2000
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(00)02152-9
Subject(s) - wortmannin , cathepsin g , chemistry , integrin , phosphatidylinositol , platelet , platelet activation , platelet glycoprotein gpiib iiia complex , phosphoinositide 3 kinase , neutrophil elastase , apyrase , ly294002 , pi , biochemistry , elastase , microbiology and biotechnology , kinase , extracellular , signal transduction , pi3k/akt/mtor pathway , biology , enzyme , receptor , immunology , inflammation
Neutrophil elastase (NE) upregulates the fibrinogen binding activity of the platelet integrin α IIb β 3 through proteolysis of the α IIb subunit. This cleavage allows a strong potentiation of platelet aggregation induced by low concentrations of cathepsin G (CG), another neutrophil serine proteinase. During this activation process, we observed a strong fibrinogen binding and aggregation‐dependent phosphatidylinositol 3,4‐ bis ‐phosphate (PtdIns(3,4)P 2 ) accumulation. PtdIns(3,4)P 2 has been suggested to play a role in the stabilization of platelet aggregation, possibly through the control of a maintained α IIb β 3 integrin activation. Here we show that inhibition of phosphoinositide 3‐kinase (PI 3‐K) by very low concentrations of wortmannin or LY294002 transformed the irreversible platelet aggregation induced by a combination of NE and low concentrations of CG into a reversible aggregation. However, although inhibition of PI 3‐K was very efficient in inducing platelet disaggregation, it did not modify the level of α IIb β 3 activation as assessed by binding of an activation‐dependent antibody. These results indicate that PI 3‐K activity can control the irreversibility of platelet aggregation even under conditions where α IIb β 3 integrin remains activated.