Abstract 476: Reduction of Platelet LOX-1 Expression by Aspirin and Pravastatin; Mechanism Relating to Nitric Oxide, Oxidative Stress and Chemokine RANTES
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a receptor for oxLDL, has been reported to play a pro-atherogenic role. It is expressed primarily on endothelial cells, and to a small extent on platelets. The surface expression of this receptor is dependent on cell activation, and binding of oxLDL to this receptor is thought to mediate platelet-endothelial cell interactions. However, the role of LOX-1 in platelet aggregation, oxidative stress and chemokine release by platelets is unclear. We measured basal and ADP-stimulated LOX-1 expression level on platelets (by flowcytometry) and its regulation by a COX-1 inhibitor, aspirin, and an HMG CoA reductase inhibitor, pravastatin. ADP stimulation increased mean fluorescence intensity (MFI) of LOX-1 expression (2.5–4.5 fold, P<0.01). Treatment with aspirin (1–10 mM) or pravastatin (1–10 μM) reduced platelet LOX-1 expression in a dose-dependent manner, with a maximum of 10-fold and 9.5-fold decrease in MFI (P100 fold decrease in LOX-1 expression, P<0.01). Further, aspirin and pravastatin treatment reduced reactive oxygen species (ROS) release by ADP-activated platelets in a dose-dependent fashion (baseline MDA 1.18±0.12 μM; after ADP stimulation 4.68±0.18 μM; after ASA treatment 1.59±0.18 μM; after pravastatin treatment 1.68±0.18 μM; combination of aspirin and pravastatin 1.38±0.06 μM) and enhanced NO release (measured as nitrite; maximum increase with ASA- 1.96 fold, maximum increase with pravastatin- 1.65 fold, P<0.02). Aspirin, but not pravastatin, also attenuated the release of platelet chemokine, RANTES. Thus, ADP upregulates platelet LOX-1 expression, and aspirin and pravastatin alone and together significantly reduce it. Our data also suggest that LOX-1 may regulate the increase in NO release together with a decrease in ROS and RANTES. .