AN ESSENTIAL ROLE FOR LYSOPHOSPHATIDYLCHOLINE IN THE INHIBITION OF PLATELET-AGGREGATION BY SECRETORY PHOSPHOLIPASE A(2)

The release of secretory phospholipase A(2) (sPLA(2)) into the mammali an circulation may contribute to the development of hemorrhagic and in flammatory diseases. sPLA(2) has previously been shown to alter the be havior of platelets, leukocytes. and endothelial cells, although the m olecular basis for these cellular effects has not been established. Ou r studies indicate that the inhibition of platelet aggregation by snak e, bee venom, and pancreatic sPLA(2) is dependent on a plasma cofactor . This cofactor resides within the lipoprotein fraction of plasma, wit h 54%, 31%, and 11% of the activity present in the high-density lipopr otein (HDL), low-density lipoprotein (LDL), and very low density lipop rotein (VLDL) fractions, respectively. Delipidation of HDL and LDL was associated with the complete loss of platelet-inhibitory activity. In cubation of purified sPLA(2) 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 agg regation. Purified lysoPC (10 to 100 mu g/ mL) inhibited platelet aggr egation and dense granule release induced by thrombin (0.05 U/mL), col lagen (1 mu g/mL), ionophore A23187 (2 mu mol/L), ADP (12.5 mu mol/L), and adrenaline (3.2 mu mol/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 enzym atic generation of lysoPC from plasma lipoproteins is essential for th e sPLA(2)-mediated inhibition of platelet activation in the presence o f albumin. These results raise the possibility that the toxic effects of circulating sPLA(2) may be due in part to the generation of the bio active lyso-phospholipid, lysoPC. (C) 1995 by The American Society of Hematology.