Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidemia.
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 non-bone 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 hyperreactivity induced by increased platelet cholesterol content. Intravital thrombosis studies demonstrated that platelet SR-BI deficiency protected mice from prothrombotic phenotype in 2 types of dyslipidemia associated with increased platelet cholesterol content. These novel findings demonstrate that SR-BI plays dual roles in thrombosis and may contribute to acute cardiovascular events in vivo in hypercholesterolemia.
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Yi
Y
Ma
Mohammad Z
MZ
Ashraf
Eugene A
EA
Podrez
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism; D003435:Crotalid Venoms / Q000494:pharmacology; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D037181:Lectins, C-Type; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009842:Oligopeptides / Q000494:pharmacology; D019007:P-Selectin / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000097:blood / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D003435:Crotalid Venoms; D037181:Lectins, C-Type; D009842:Oligopeptides; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C455901:alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine; C028890:convulxin; D000244:Adenosine Diphosphate; D002784:Cholesterol