Deletion of the High-Density Lipoprotein Receptor Scavenger Receptor BI in Mice Modulates Thrombosis Susceptibility and Indirectly Affects Platelet Function by Elevation of Plasma Free Cholesterol

Objective—Scavenger receptor BI (SR-BI) is a cell surface receptor that promotes the selective uptake of cholesteryl esters from high-density lipoprotein (HDL) by the liver. In mice, SR-BI deficiency results in increased plasma HDL cholesterol levels and enhanced susceptibility to atherosclerosis. The aim of this study was to investigate the role of SR-BI deficiency on platelet function. Methods and Results—SR-BI-deficient mice were thrombocytopenic, and their platelets were abnormally large, probably because of an increased cholesterol content. The FeCl3 acute injury model to study arterial thrombosis susceptibility showed that SR-BI wild-type mice developed total arterial occlusion after 24±2 minutes. In SR-BI-deficient mice, however, the time to occlusion was reduced to 13±1 minutes (P=0.02). Correspondingly, in SR-BI-deficient mice, platelets circulated in an activated state and showed increased adherence to immobilized fibrinogen. In contrast, platelet-specific disruption of SR-BI by bone marrow transplantation in wild-type mice did not alter plasma cholesterol levels or affect platelet count, size, cholesterol content, or reactivity, suggesting that changes in plasma cholesterol levels were responsible for the altered responsiveness of platelets in SR-BI-deficient mice. Conclusion—The function of SR-BI in HDL cholesterol homeostasis and prevention of atherosclerosis is indirectly also essential for maintaining normal platelet function and prevention of thrombosis.

[1]  M. Krieger,et al.  Thrombocytopenia and Platelet Abnormalities in High-Density Lipoprotein Receptor–Deficient Mice , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[2]  J. Akkerman,et al.  Role of membrane cholesterol in platelet calcium signalling in response to VWF and collagen under stasis and flow , 2008, Thrombosis and Haemostasis.

[3]  A. Assinger,et al.  Oxidation by hypochlorite converts protective HDL into a potent platelet agonist , 2008, FEBS letters.

[4]  S. Mundell,et al.  Reciprocal regulation of platelet responses to P2Y and thromboxane receptor activation , 2008, Journal of thrombosis and haemostasis : JTH.

[5]  P. Siljander,et al.  Platelet receptor recognition and cross‐talk in collagen‐induced activation of platelets , 2007, Journal of thrombosis and haemostasis : JTH.

[6]  C. Mineo,et al.  Role of high-density lipoprotein and scavenger receptor B type I in the promotion of endothelial repair. , 2007, Trends in cardiovascular medicine.

[7]  T. V. van Berkel,et al.  HDL cholesterol levels are an important factor for determining the lifespan of erythrocytes. , 2005, Experimental hematology.

[8]  T. V. van Berkel,et al.  Scavenger receptor class B type I is solely responsible for the selective uptake of cholesteryl esters from HDL by the liver and the adrenals in mice Published, JLR Papers in Press, August 16, 2004. DOI 10.1194/jlr.M400191-JLR200 , 2004, Journal of Lipid Research.

[9]  T. V. van Berkel,et al.  Dual role for scavenger receptor class B, type I on bone marrow-derived cells in atherosclerotic lesion development. , 2004, The American journal of pathology.

[10]  T. V. van Berkel,et al.  Differential Effects of Scavenger Receptor BI Deficiency on Lipid Metabolism in Cells of the Arterial Wall and in the Liver* , 2003, Journal of Biological Chemistry.

[11]  J. Slot,et al.  Concentration of rafts in platelet filopodia correlates with recruitment of c‐Src and CD63 to these domains , 2003, Journal of thrombosis and haemostasis : JTH.

[12]  T. Ishida,et al.  Expression of Human Scavenger Receptor B1 on and in Human Platelets , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[13]  P. Yancey,et al.  Importance of different pathways of cellular cholesterol efflux. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[14]  B. Payrastre,et al.  Lipid rafts are critical membrane domains in blood platelet activation processes. , 2003, Biochimica et biophysica acta.

[15]  Zaverio M. Ruggeri,et al.  Platelets in atherothrombosis , 2002, Nature Medicine.

[16]  N. Andrews,et al.  Failure of red blood cell maturation in mice with defects in the high-density lipoprotein receptor SR-BI. , 2002, Blood.

[17]  V. C. Yang,et al.  Identification and expression of scavenger receptor SR-BI in endothelial cells and smooth muscle cells of rat aorta in vitro and in vivo. , 2002, Atherosclerosis.

[18]  M. Krieger,et al.  Loss of SR-BI Expression Leads to the Early Onset of Occlusive Atherosclerotic Coronary Artery Disease, Spontaneous Myocardial Infarctions, Severe Cardiac Dysfunction, and Premature Death in Apolipoprotein E-Deficient Mice , 2002, Circulation research.

[19]  H. Rayburn,et al.  Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)-deficient mice. , 2001, The Journal of clinical investigation.

[20]  José A Fernández,et al.  Plasma Lipoproteins, Hemostasis and Thrombosis , 2001, Thrombosis and Haemostasis.

[21]  G. FitzGerald,et al.  Endogenous biosynthesis of thromboxane and prostacyclin in 2 distinct murine models of atherosclerosis. , 2000, Blood.

[22]  G. Reed,et al.  Molecular mechanisms of platelet exocytosis: insights into the "secrete" life of thrombocytes. , 2000, Blood.

[23]  M. Krieger,et al.  Scavenger Receptor Class B, Type I-mediated [3H]Cholesterol Efflux to High and Low Density Lipoproteins Is Dependent on Lipoprotein Binding to the Receptor* , 2000, The Journal of Biological Chemistry.

[24]  A. Tedgui,et al.  CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. , 2000, Circulation.

[25]  H. Hobbs,et al.  Transport of Lipids from High and Low Density Lipoproteins via Scavenger Receptor-BI* , 1999, The Journal of Biological Chemistry.

[26]  S. Kaul,et al.  Evidence that high-density lipoprotein cholesterol is an independent predictor of acute platelet-dependent thrombus formation. , 1999, The American journal of cardiology.

[27]  A. Rigotti,et al.  Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  J. Hartwig,et al.  The Elegant Platelet: Signals Controlling Actin Assembly , 1999, Thrombosis and Haemostasis.

[29]  K. Matsumoto,et al.  Expression of human scavenger receptor class B type I in cultured human monocyte-derived macrophages and atherosclerotic lesions. , 1999, Circulation research.

[30]  S. Gordon,et al.  Recent progress in defining the role of scavenger receptors in lipid transport, atherosclerosis and host defence. , 1998, Current opinion in lipidology.

[31]  G. Lowe,et al.  Effects of lipids and lipoproteins on thrombosis and rheology. , 1998, Atherosclerosis.

[32]  G. Assmann,et al.  HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinositide-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[33]  P. Carmeliet,et al.  Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice. , 1998, Circulation.

[34]  A. Rigotti,et al.  A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  G. Davı̀,et al.  Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. , 1997, Circulation.

[36]  A. Rigotti,et al.  Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. , 1996, The Journal of clinical investigation.

[37]  Helen H. Hobbs,et al.  Identification of Scavenger Receptor SR-BI as a High Density Lipoprotein Receptor , 1996, Science.

[38]  G. Assmann,et al.  HDL3 activates phospholipase D in normal but not in glycoprotein IIb/IIIa-deficient platelets. , 1995, Biochemical and biophysical research communications.

[39]  J. Goudemand,et al.  Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[40]  C. Patrono.  Aspirin as an antiplatelet drug. , 1994, The New England journal of medicine.

[41]  D. Betteridge,et al.  Platelet function in patients with hypercholesterolaemia , 1994, European journal of clinical investigation.

[42]  M. Reilly,et al.  Cellular activation by thromboxane A2 and other eicosanoids. , 1993, European heart journal.

[43]  J. Hoxie,et al.  Signaling through G Proteins and G Protein-coupled Receptors during Platelet Activation , 1993, Thrombosis and Haemostasis.

[44]  A. von Eckardstein,et al.  Lecithin: cholesterol acyltransferase deficiency and fish-eye disease , 1991 .

[45]  G. Sandusky,et al.  Rat model of arterial thrombosis induced by ferric chloride. , 1990, Thrombosis research.

[46]  K. Cadigan,et al.  Isolation and characterization of Chinese hamster ovary cell mutants defective in intracellular low density lipoprotein-cholesterol trafficking , 1990, The Journal of cell biology.

[47]  G. Jamieson,et al.  Thrombin binding and response in platelets from patients with dyslipoproteinemias: increased stimulus-response coupling in type II hyperlipoproteinemia. , 1986, Blood.

[48]  C. Vergani,et al.  Bile lipid composition and haemostatic variables in a case of high density lipoprotein deficiency (Tangier disease) , 1984, European journal of clinical investigation.

[49]  T. Gotoda.  [Lecithin-cholesterol acyltransferase deficiency and fish eye disease]. , 1998, Ryoikibetsu shokogun shirizu.

[50]  J. Mehta,et al.  Inhibitory effect of high-density lipoprotein on platelet function is mediated by increase in nitric oxide synthase activity in platelets. , 1994, Life sciences.

[51]  E. Salzman,et al.  Platelet interaction with artificial surfaces: in vitro evaluation. , 1989, Methods in enzymology.

[52]  E. Gjone,et al.  Familial plasma lecithin: cholesterol acyltransferase deficiency. A study of the platelets. , 1971, Scandinavian journal of clinical and laboratory investigation.