Coordinated inhibition of actin-induced platelet aggregation by plasma
gelsolin and vitamin D-binding protein
CA Vasconcellos and SE Lind
Experimental Medicine Division, Brigham and Women's Hospital, Boston, MA
02115.
Actin is an abundant intracellular protein that is released into the blood
during tissue injury and its injection into rats causes microthrombi to
form in the vasculature. This report and others have shown that actin
filaments are able to aggregate platelets in an adenosine diphosphate
(ADP)-dependent manner. The effects on this process of two plasma
actin-binding proteins, vitamin D-binding protein (DBP) and gelsolin, were
examined separately and together. The addition of DBP, a monomer-binding
protein, to actin filaments did not affect their ability to induce platelet
aggregation. However, severing of actin filaments with gelsolin resulted in
an increased degree of platelet aggregation. Preincubation of F-actin with
both gelsolin and DBP resulted in a significant inhibition of aggregation.
The effects of DBP and gelsolin on actin-induced aggregation paralleled
their effects on exchange of actin-bound adenine nucleotides. DBP inhibited
1, N6- ethenoadenosine 5' triphosphate (epsilon-ATP) exchange with G-actin
but not with F-actin. Gelsolin increased epsilon-ATP exchange with F-actin,
which was largely abrogated by the addition of DBP. These results suggest
that gelsolin's severing (and subsequent capping) of actin filaments not
only results in an increase in the number of pointed filament ends but also
in the dissociation of actin monomers containing ADP. Phalloidin, which
stabilizes actin filaments while decreasing both monomer and nucleotide
exchange, inhibited actin-induced aggregation, as well, indicating that
depolymerization of actin filaments is not required to inhibit aggregation.
Platelet activation by either G- or F- actin may thus be regulated by the
local concentrations of the plasma actin-binding proteins gelsolin and DBP.
Together, these proteins inhibit platelet aggregation in a manner that can
be explained by their effects on actin's filament structure and the
accessibility of its bound ADP. Depletion of DBP or gelsolin may allow
actin released from injured tissues to stimulate purinergic receptors on
platelets, and perhaps other cells, via its bound adenine nucleotides.
Volume 82,
Issue 12,
pp. 3648-3657,
12/15/1993
Copyright © 1993 by The American Society of Hematology
