We identified a family with a functional mutation in SR-BI. The mutation carriers had increased HDL cholesterol levels and a reduction in cholesterol efflux from macrophages but no significant increase in atherosclerosis. Reduced SR-BI function was associated with altered platelet function and decreased adrenal steroidogenesis. (Funded by the European Community and others.).

Platelets and coagulation factors are involved in the process of haemostasis, which ensures undisturbed blood flow upon vessel wall damage. However, excessive platelet aggregation and/or coagulation may lead to arterial or venous thrombosis. Pro-atherogenic lipoproteins, including native and oxidized low-density lipoprotein (LDL), are associated with an increased susceptibility to thrombosis. In contrast, numerous epidemiological studies have established an inverse correlation between high-density lipoprotein (HDL) levels and the risk for thrombosis. In addition to its role in reverse cholesterol transport, HDL also interacts with platelets, the coagulation cascade, and the vascular endothelium. Native HDL prevents platelet hyperreactivity by limiting intraplatelet cholesterol overload, as well as by modulating platelet signalling pathways after binding platelet HDL receptors such as scavenger receptor class B type I (SR-BI) and apoER2'. The antithrombotic properties of native HDL are also related to the suppression of the coagulation cascade and stimulation of clot fibrinolysis. Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL's antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis.

Objective-The interaction of platelets with low density lipoprotein (LDL) contributes to the development of cardiovascular disease. Platelets are activated by native LDL (nLDL) through apoE Receptor 2Ј (apoER2Ј)-mediated signaling to p38 MAPK and by oxidized LDL (oxLDL) through lysophosphatidic acid (LPA) signaling to Rho A and Ca 2ϩ . Here we report a new mechanism for platelet activation by oxLDL. Methods and Results-Oxidation of nLDL increases p38MAPK activation through a mechanism that is (1) independent of LPA, and (2) unlike nLDL-signaling not desensitized by prolonged platelet-LDL contact or inhibited by receptorassociated protein or chondroitinase ABC. Antibodies against scavenger receptors CD36 and SR-A alone fail to block p38 MAPK activation by oxLDL but combined blockade inhibits p38 MAPK by Ͼ40% and platelet adhesion to fibrinogen under flow by Ͼ60%. Mouse platelets deficient in either CD36 or SR-A show normal p38 MAPK activation by oxLDL but combined deficiency of CD36 and SR-A disrupts oxLDL-induced activation of p38 MAPK by Ͼ70%. Key Words: platelets Ⅲ LDL Ⅲ oxidized LDL Ⅲ CD36 Ⅲ scavenger receptor-A A n elevated level of native low density lipoprotein (nLDL) is a risk factor for arterial thrombosis and atherosclerosis as demonstrated in familial hypercholesterolemia, where defective apoB/E receptors fail to remove nLDL from the circulation. Atherogenesis starts when nLDL accumulates in the vessel wall at sites of injury and is oxidized by products from macrophages, smooth muscle cells, and endothelial cells. 1 Oxidized LDL (oxLDL) accumulates in monocytes that have infiltrated the subendothelium and differentiated into macrophages. The resulting foam cells are characteristic for the early atherosclerotic lesion. 2 OxLDL further contributes to atherosclerosis because it contains lysophosphatidic acid (LPA), which starts platelet shape change and aggregation. 3 In healthy individuals, the concentration of oxLDL is low. The normal intima contains little oxLDL (1.86Ϯ0.59 ng/g apolipoprotein B100 [apoB100]) but levels increase 6-fold in atherosclerotic lesions (11.9Ϯ1.7 ng/g apoB100). 4 Blood from atherosclerotic patients contains autoantibodies that react with oxidation-specific epitopes in both the lipid and protein moiety of oxLDL, 5,6 indicating that oxLDL is also present in the circulation. Hence, in the circulation, platelets can come into contact with oxLDL and become activated, thereby contributing to thrombotic occlusion. Conclusion-TheseThe oxidation of nLDL in vivo can be mimicked in vitro by treatment of nLDL with FeSO 4 . These oxLDL preparations resemble in vivo oxidized LDL with respect to electrophoretic mobility, density, LPA content, fragmentation of apoB100, chemotactic activity for monocytes, and susceptibility to degradation by macrophages. 3,7-9 LPA makes oxLDL a potent platelet activating agent 3 through activation of its LPA 1 and LPA 3 receptors, 10 which are members of the endothelial differentiation gene receptor family. At low concentrations, LPA stimulates Rho, Rho-ki...