The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors

Abstract

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 P2Y 1 and P2Y 12 . 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 P2Y 1 and P2Y 12 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 P2Y 1 and P2Y 12 receptors might be useful preventing LPA-elicited thrombus formation in patients with cardiovascular

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…The activation of platelets via chemokines and low levels of primary agonists such as ADP have been shown to be dependent on the purinergic P2Y 1 receptor rather than the P2Y 12 receptor , which is believed to have a greater role in sustained thrombus formation (Leon et al, 2003;Nylander et al, 2003;Mazzucato et al, 2004). Furthermore, P2Y 1 is involved in platelet-monocyte complex formation when platelets are stimulated by lysophosphatidic acid (Haseruck et al, 2004). Although the phenomenon of platelet-leukocyte complex formation and adhesion has not been tested after platelet activation via chemokines, ADP signalling through P2Y 1 may contribute to the initial stages of platelet activation in an inflammatory setting.…”

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

“…LPA 5 couples to G 12/13 -mediated Rho activation and G q -mediated phospholipase C activation. Similarly in platelets, LPA stimulates Rho and Ca 2ϩ mobilization; low LPA concentrations induce Rho/ Rho kinase-mediated shape change, and higher LPA concentrations stimulate an increase of cytosolic Ca 2ϩ and aggregation (25)(26)(27)(28). LPA 5 can also mediate an increase in intracellular cAMP production independent of G s (18), and cAMP formation inhibits platelet activation, which implies that LPA 5 activation could inhibit platelet aggregation.…”

Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

“…The exposure of human platelets to LPA triggers shape change (3)(4)(5), fibronectin matrix assembly (6), and platelet-leukocyte interactions (7). LPA is also a weak activator of human platelet aggregation and potentiates the effects of other agonists such as ADP and epinephrine (3,8,9); although interestingly, platelets isolated from ϳ20% of normal donors are selectively unresponsive to LPA (10,11).…”