The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors.
Despite the fact that lysophosphatidic acid (LPA) has been identified as a main platelet-activating lipid of mildly oxidized low-density lipoprotein (LDL) and human atherosclerotic lesions, it remains unknown whether it is capable of activating platelets in blood. We found that LPA at concentrations slightly above plasma levels induces platelet shape change, aggregation, and platelet-monocyte aggregate formation in blood. 1-alkyl-LPA (16:0 fatty acid) was almost 20-fold more potent than 1-acyl-LPA (16:0). LPA directly induced platelet shape change in blood and platelet-rich plasma obtained from all blood donors. However, LPA-stimulated platelet aggregation in blood was donor dependent. It could be completely blocked by apyrase and antagonists of the platelet adenosine diphosphate (ADP) receptors P2Y1 and P2Y12. These substances also inhibited LPA-induced aggregation of platelet-rich plasma and aggregation and serotonin secretion of washed platelets. These results indicate a central role for ADP-mediated P2Y1 and P2Y12 receptor activation in supporting LPA-induced platelet aggregation. Platelet aggregation and platelet-monocyte aggregate formation stimulated by LPA was insensitive to inhibition by aspirin. We conclude that LPA at concentrations approaching those found in vivo can induce platelet shape change, aggregation, and platelet-monocyte aggregate formation in whole blood and suggest that antagonists of platelet P2Y1 and P2Y12 receptors might be useful preventing LPA-elicited thrombus formation in patients with cardiovascular diseases.
Haserück
Nadine
N
Institute for Prevention of Cardiovascular Diseases, University of Munich, Germany.
Erl
Wolfgang
W
Pandey
Dharmendra
D
Tigyi
Gabor
G
Ohlmann
Philippe
P
Ravanat
Catherine
C
Gachet
Christian
C
Siess
Wolfgang
W
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001157:Arterial Occlusive Diseases / Q000097:blood*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008246:Lysophospholipids / Q000494:pharmacology* / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction
D008246:Lysophospholipids; D008565:Membrane Proteins; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; C032881:lysophosphatidic acid