Increased phosphatidic acid and decreased lysophosphatidic acid in response to thrombin is associated with inhibition of platelet aggregation.
Thromboxane A2, produced from the arachidonic acid released from platelet phospholipids by phospholipase A2, stimulates platelet aggregation. It remains unresolved whether additional products of platelet phospholipase A2 might promote aggregation. To address this question, we have used aspirin-treated platelets to block thromboxane A2 formation and studied the influence of the phospholipase A2 inhibitor U10029A on platelet aggregation and secretion in response to thrombin. U10029A at 100 microM markedly inhibited platelet aggregation, but had no effect on platelet secretion. Since this concentration of U10029A effectively blocked lysophosphatidic acid (LPA) formation, LPA was added and found to substantially reverse the inhibitory effect of U10029A in these platelets. Furthermore, the action of U10029A was not due to inhibition of phosphatidate phosphohydrolase because U10029A, unlike propranolol, did not inhibit this enzyme. Although it is not possible to conclusively rule out an effect of U10029A in addition to its inhibition of phospholipase A2, our results reveal that a product of phospholipase A2 other than thromboxane A2 is important for platelet aggregation, but not for secretion in response to thrombin. Our data suggest that this product is LPA. Since the amount of phosphatidic acid (PA) increased dramatically concurrent with inhibition of platelet aggregation, it is safe to conclude that PA has no direct role to promote platelet aggregation in response to thrombin.
Gerrard
J M
JM
Manitoba Institute of Cell Biology, Winnipeg, Canada.
Robinson
P
P
Narvey
M
M
McNicol
A
A
D016718:Arachidonic Acid / Q000097:blood; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008246:Lysophospholipids / Q000097:blood* / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000097:blood* / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000097:blood
D008246:Lysophospholipids; D010712:Phosphatidic Acids; D010975:Platelet Aggregation Inhibitors; D011412:Propanolamines; D016718:Arachidonic Acid; D013928:Thromboxane A2; C044751:U 10029A; D010741:Phospholipases A; D054467:Phospholipases A2; D013917:Thrombin; D001241:Aspirin