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Haserück, Nadine (2007): Platelet activation and platelet-monocyte aggregate formation by the atherosclerotic plaque lipid lysophosphatidic acid. Dissertation, LMU München: Faculty of Medicine



Oxidized LDL and platelets play a central role in the pathogenesis of atherosclerosis and ischemic cardiovascular diseases. Lysophosphatidic acid (LPA) is a thrombogenic substance that accumulates in mildly-oxidized LDL and in human atherosclerotic lesions, and is responsible for the initial platelet activation, shape change, induced by mildly-oxidized LDL and extracts of lipid-rich atherosclerotic plaques (Siess et al., 1999 Proc Natl Acad Sci USA 1999). LPA directly induced platelet shape change in blood and platelet-rich plasma (PRP) obtained from all blood donors. Albumin was one of the main inhibiting factors of platelet shape change in plasma. Interestingly LPA, at concentrations slightly above plasma levels, induced platelet shape change and aggregation in blood. 1-alkyl-LPA (16:0) was almost 20-fold more potent than 1-acyl-LPA (16:0). LPA-stimulated platelet aggregation in blood and PRP was donor-dependent. LPA-induced aggregation in blood could be completely blocked by the ADP- scavenging enzyme, apyrase, and antagonists of the platelet 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 and show that LPA synergistically with ADP induces platelet aggregation in blood. Thus antagonists of platelet P2Y1 and P2Y12 receptors, especially in donors highly sensitive to LPA, might be useful in preventing LPA-elicited thrombus formation in patients with cardiovascular diseases. The mechanism of LPA plus ADP-induced aggregation was independent of the Rho/Rho kinase pathway which mediated LPA-induced platelet shape change in blood. LPA, activating G13, but not Gi or Gq synergized also with epinephrine, activating Gi, and serotonin, activating Gq, in amplifying LPA-induced platelet aggregation in washed platelets. LPA/serotonin-induced aggregation was blocked by either ADP-receptor antagonist whereas synergistic aggregation induced by LPA/epinephrine was independent from ADP-receptor antagonists. The latter results demonstrate an additional mechanism for aggregation independent of P2Y1 and P2Y12. Most surprising, LPA-induced platelet aggregation was insensitive to inhibition by aspirin. LPA at low concentrations, starting slightly above plasma level, was also capable of eliciting platelet-monocyte conjugate formation. LPA-induced platelet-monocyte formation was independent of the blood donor. ADP mediated P2Y1 and P2Y12 receptor activation played only a minor role. Platelet-monocyte aggregate formation stimulated by LPA was P-selectin-mediated and insensitive to inhibition by aspirin. Pathophysiolocical events such as sudden plaque rupture or progressive enrichment of circulating oxidized LDL at critical sites of turbulent flow might lead to higher local blood concentration of LPA. This can induce platelet shape change, platelet aggregation and platelet-monocyte formation at atherosclerotic sites. LPA receptor antagonists could be of possible benefit not only preventing arterial thrombosis, but also retarding vascular inflammation in patients with cardiovascular disease.