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.


RESULTS
SR-BI-deficient mice were thrombocytopenic, and their platelets were abnormally large, probably because of an increased cholesterol content. The FeCl(3) 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.


CONCLUSIONS
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.
Leiden/Amsterdam Center for Drug Research, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC, Leiden, the Netherlands. skorporaal@lacdr.leidenuniv.nl
Suzanne J A
SJ
Korporaal
Illiana
I
Meurs
Arnaud D
AD
Hauer
Reeni B
RB
Hildebrand
Menno
M
Hoekstra
Hugo Ten
HT
Cate
Domenico
D
Praticò
Jan-Willem N
JW
Akkerman
Theo J C
TJ
Van Berkel
Johan
J
Kuiper
Miranda
M
Van Eck
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002712:Chlorides; D002791:Cholesterol, Dietary / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D004195:Disease Models, Animal; D005290:Ferric Compounds; D005340:Fibrinogen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D051122:Scavenger Receptors, Class B / Q000172:deficiency* / Q000235:genetics; D013921:Thrombocytopenia / Q000378:metabolism / Q000473:pathology; D013927:Thrombosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D015854:Up-Regulation
D002712:Chlorides; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D005290:Ferric Compounds; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D005340:Fibrinogen; C024555:ferric chloride