TY - JOUR T1 - Modulation of ADP-Induced Platelet Activation by Aspirin and Pravastatin: Role of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1, Nitric Oxide, Oxidative Stress, and Inside-Out Integrin Signaling JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1324 LP - 1332 DO - 10.1124/jpet.107.122853 VL - 322 IS - 3 AU - Muhammad R. Marwali AU - Chang-Ping Hu AU - Bhavna Mohandas AU - Abhijit Dandapat AU - Prabhakar Deonikar AU - Jiawei Chen AU - Ian Cawich AU - Tatsuya Sawamura AU - Mahendra Kavdia AU - Jawahar L. Mehta Y1 - 2007/09/01 UR - http://jpet.aspetjournals.org/content/322/3/1324.abstract N2 - Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a receptor for oxidized-LDL, is up-regulated in activated endothelial cells, and it plays a role in atherothrombosis. However, its role in platelet aggregation is unclear. Both aspirin and HMG CoA reductase inhibitors (statins) reduce LOX-1 expression in endothelial cells. In this study, we investigated the effect of aspirin and pravastatin on LOX-1 expression on plate-lets. After ADP stimulation, mean fluorescence intensity of LOX-1 expression on platelets increased 1.5- to 2.0-fold. Blocking LOX-1 inhibited ADP-induced platelet aggregation in a concentration- and time-dependent manner. We also established that LOX-1 is important for ADP-stimulated inside-out activation of platelet αIIbβ3 and α2β1 integrins (fibrinogen receptors). The specificity of this interaction was determined by arginine-glycine-aspartate-peptide inhibition. Furthermore, we found that LOX-1 inhibition of integrin activation is mediated by inhibition of protein kinase C activity. In other experiments, treatment with aspirin (1–10 mM) and pravastatin (1–5 μM) reduced platelet LOX-1 expression, with a synergistic effect of the combination of aspirin and pravastatin. Aspirin and pravastatin both reduced reactive oxygen species (ROS) released by activated platelets measured as malonyldialdehyde (MDA) release and nitrate/nitrite ratio. Aspirin and pravastatin also enhanced nitric oxide (NO) release measured as nitrite/nitrite + nitrate (NOx) ratio in platelet supernates. Small concentrations of aspirin and pravastatin had a synergistic effect on the inhibition of MDA release and enhancement of nitrite/NOx. Thus, LOX-1 is important for ADP-mediated platelet integrin activation, possibly through protein kinase C activation. Furthermore, aspirin and pravastatin inhibit LOX-1 expression on platelets in part by favorably affecting ROS and NO release from activated platelets. ER -