Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidemia

Abstract

Hypercholesterolemia is associated with increased platelet sensitivity to agonists and a prothrombotic phenotype. Mechanisms of platelet hypersensitivity are poorly understood; however, increased platelet cholesterol levels associated with hypercholesterolemia were proposed as leading to hypersensitivity. Scavenger receptor class B type I (SR-BI) in the liver controls plasma high-density lipoprotein (HDL) levels, and SR-BI-deficient mice display a profound dyslipoproteinemia. SR-BI is also expressed on platelets, and recent studies have suggested a role for SR-BI in platelet function; however, its role in hemostasis is unknown. Our present studies demonstrated that nonbone marrow-derived SR-BI deficiency and the dyslipidemia associated with it lead to platelet hyperreactivity that was mechanistically linked to increased platelet cholesterol content. Platelet-specific deficiency of SR-BI, on the other hand, was associated with resistance to hyper- IntroductionDyslipidemia is frequently associated with increased platelet reactivity and thrombogenic potential. [1][2][3][4][5] Although subjects with increased measures of platelet reactivity are at increased prospective risk for coronary events and death, 3,6-9 the mechanisms modulating platelet reactivity in vivo during dyslipidemia are still poorly understood. A mechanistic link between oxidative stress associated with dyslipidemia and a prothrombotic phenotype have been recently established by us. 10 Our studies demonstrated that specific oxidized phospholipids accumulate in plasma in dyslipidemia and interact with platelet CD36, leading to enhanced platelet reactivity, activation, and thrombosis. 10 Dyslipidemia is associated with changes in cellular cholesterol balance leading, in some cases, to increases in platelet cholesterol content or cholesterol/phospholipids ratio. A direct role of excessive platelet cholesterol in induction of platelet hyperreactivity has been shown. 1,2,11,12 However, the molecular mechanisms and pathways linking increased platelet reactivity and cholesterol levels in platelets are not well understood. One critical player in cholesterol metabolism is scavenger receptor class B type I (SR-BI), a multiligand receptor of the CD36 superfamily. 13 Its major physiologic function is selective uptake of cholesteryl esters from high-density lipoprotein (HDL) in steroidogenic tissues and liver. 13 SR-BI also stimulates the bidirectional flux of free cholesterol between cells and lipoproteins, modifies membrane cholesterol distribution, and induces signaling events. 14 SR-BI-deficient mice are hypercholesterolemic with abnormally large circulating HDL particles. 15 Platelets of SR-BI-deficient mice exhibit abnormally high unesterified cholesterol, abnormal morphologies, and elevated rates of clearance from the circulation. 16 Surprisingly, despite high platelet cholesterol content, platelets of SR-BIdeficient mice exhibited in vitro either normal or blunted aggregation responses to agonist. 16 Recent studies have shown that SR-BI is exposed on re...

Adrenal-Specific Scavenger Receptor BI Deficiency Induces Glucocorticoid Insufficiency and Lowers Plasma Very-Low-Density and Low-Density Lipoprotein Levels in Mice

“…This is in accordance with findings by Dole et al, 13 Ma et al, 15 Hildebrand et al, 44 and El Bouhassani et al, 45 which showed that the relatively highplasma-free cholesterol levels/enhanced free cholesterol to total cholesterol ratio is primary responsible for the different blood cell abnormalities.…”

“…[11][12][13][14][15] Interestingly, the highest protein expression of SR-BI in mice has not been found in the liver but rather in the adrenals. 16 SR-BI protein expression is specifically localized to adrenocortical cells within the glucocorticoid hormoneproducing zona fasciculata of the adrenals.…”

Regulation of Cell Adhesion and Migration by Kindlin-3 Cleavage by Calpain

“…Human venous blood was drawn from healthy donors into acid-citratedextrose (ACD; 85 mM trisodium citrate, 65 mM citric acid, and 111 mM D-glucose, pH 4.6) solution containing prostaglandin I 2 , (1 g/ml of ACD). Gel-filtered platelets were isolated as described previously (17). Platelet counts were assessed by a Cellometer TM Auto-M10 from Nexcelom Bioscience (Lawrence, MA).…”

Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE−/− mice and activate platelets via TLR2

“…17,18 To assess whether these receptors play a role in the effects of CAP-PEs on platelets, we first tested the effect of Fab fragments of anti-CD36 and anti-SR-BI blocking antibodies on CAP-PE-induced human platelet activation. We found no significant effect of either of the blocking antibodies (supplemental Figure 4A-B).…”