Abstract 3736: The HDL Receptor SR-BI Modulates Platelet Function and Susceptibility to Thrombosis in vivo

Abstract

Objective: Scavenger receptor BI (SR-BI) is a cell surface receptor that promotes the selective uptake of cholesteryl esters from HDL by the liver. In mice, SR-BI deficiency leads to increased plasma HDL cholesterol levels and enhanced susceptibility to atherosclerosis. Recently, a family was identified in which heterozygous carriers of a mutation (P297S) in SR-BI showed elevated HDL cholesterol levels, suggesting that SR-BI is equally important in controlling HDL cholesterol levels in humans. Interestingly, SR-BI is also expressed on platelets, which play a crucial role in atherothrombosis. The aim of this study was to investigate the role of SR-BI in platelet function in both SR-BI knockout (KO) mice and human P297S carriers. Methods & Results: Hematological analysis showed that SR-BI deficiency in mice caused thrombocytopenia (381±69x10 9 SR-BI KO platelets/L vs 878±162x10 9 wildtype (WT) platelets/L, p=0.001). Correspondingly, SR-BI deficiency increased tail bleeding times from 85±8 to 134±16 sec (p=0.02). SR-BI KO platelets were abnormally large (7.1±0.3 fl vs 5.8±0.0 fl for WT platelets, p=0.0004), probably caused by an increased cholesterol content. Platelet count and size of the human P297S carriers were, however, not significantly different from matched controls. The FeCl 3 acute injury model was used to study the effect of SR-BI deficiency in mice on the susceptibility to arterial thrombosis. WT mice developed total arterial occlusion after 24±2 min. In SR-BI KO mice, however, the time to total arterial occlusion was reduced 2-fold to 13±1 min (p=0.02). In line with this finding, SR-BI KO and P297S platelets circulated in an activated state and showed increased adherence to immobilized fibrinogen. The activated state of the platelets in vivo led to desensitization of the receptors for ADP and thromboxane that are essential for positive feedback mechanisms to enhance the platelet response. As a result, ex vivo aggregation of platelets from SR-BI KO mice and P297S carriers was inhibited in response to agonist stimulation as compared to control platelets. Conclusion: SR-BI is not only essential for HDL cholesterol homeostasis and atherosclerosis susceptibility, but also for maintaining normal platelet aggregation and prevention of thrombosis.