Phosphoinositide 3-kinase inhibition reverses platelet aggregation triggered by the combination of the neutrophil proteinases elastase and cathepsin G without impairing alpha(IIb)beta(3) integrin activation
C. Trumel et al., Phosphoinositide 3-kinase inhibition reverses platelet aggregation triggered by the combination of the neutrophil proteinases elastase and cathepsin G without impairing alpha(IIb)beta(3) integrin activation, FEBS LETTER, 484(3), 2000, pp. 184-188
Neutrophil elastase (NE) upregulates the fibrinogen binding activity of the
platelet integrin alpha (IIb)beta (3) through proteolysis of the alpha (II
b) subunit, This cleavage allows a strong potentiation of platelet aggregat
ion induced by ion concentrations of cathepsin G (CG), another neutrophil s
erine proteinase, During this activation process, we observed a strong fibr
inogen binding and aggregation-dependent phosphatidylinositol 3,4-bis-phosp
hate (PtdIns(3,4)P-2) accumulation. PtdIns(3,4)P-2 has been suggested to pl
ay a role in the stabilization of platelet aggregation, possibly through th
e control of a maintained alpha (IIb)beta (3) integrin activation, Here we
show that inhibition of phosphoinositide 3-kinase (PI 3-K) by very low conc
entrations of wortmannin of LY294002 transformed the irreversible platelet
aggregation induced by a combination of NE and low concentrations of CG int
o a reversible aggregation. However, although inhibition of PI 3-K was very
efficient in inducing platelet disaggregation, it did not modify the level
of alpha (IIb)beta (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 al
pha (IIb)beta (3) integrin remains activated. (C) 2000 Federation of Europe
an Biochemical Societies. Published by Elsevier Science B.V, All rights res
erved.