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An essential role for lysophosphatidylcholine in the inhibition of platelet
aggregation by secretory phospholipase A2
Y Yuan, SP Jackson, HH Newnham, CA Mitchell and HH Salem
Department of Medicine, Monash University, Box Hill Hospital, Victoria,
Australia.
The release of secretory phospholipase A2 (sPLA2) into the mammalian
circulation may contribute to the development of hemorrhagic and
inflammatory diseases. sPLA2 has previously been shown to alter the
behavior of platelets, leukocytes, and endothelial cells, although the
molecular basis for these cellular effects has not been established. Our
studies indicate that the inhibition of platelet aggregation by snake, bee
venom, and pancreatic sPLA2 is dependent on a plasma cofactor. This
cofactor resides within the lipoprotein fraction of plasma, with 54%, 31%,
and 11% of the activity present in the high- density lipoprotein (HDL),
low-density lipoprotein (LDL), and very low density lipoprotein (VLDL)
fractions, respectively. Delipidation of HDL and LDL was associated with
the complete loss of platelet-inhibitory activity. Incubation of purified
sPLA2 with the HDL fraction of plasma resulted in the time-dependent
generation of lysophosphatidylcholine (lysoPC). The formation of lysoPC
correlated with the inhibition of platelet aggregation. Purified lysoPC (10
to 100 micrograms/mL) inhibited platelet aggregation and dense granule
release induced by thrombin (0.05 U/mL), collagen (1 micrograms/mL),
ionophore A23187 (2 mumol/L), ADP (12.5 mumol/L), and adrenaline (3.2
mumol/L). The inhibition of platelet aggregation by lysoPC was
dose-dependent and correlated with decreased fibrinogen binding to
glycoprotein IIb-IIIa. Our studies indicate that the enzymatic generation
of lysoPC from plasma lipoproteins is essential for the sPLA2-mediated
inhibition of platelet activation in the presence of albumin. These results
raise the possibility that the toxic effects of circulating sPLA2 may be
due in part to the generation of the bioactive lysophospholipid, lysoPC.
Volume 86,
Issue 11,
pp. 4166-4174,
12/01/1995
Copyright © 1995 by The American Society of Hematology
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