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.
Ma
Yi
Y
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Ashraf
Mohammad Z
MZ
Podrez
Eugene A
EA
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