Extrahepatic high-density lipoprotein receptor SR-BI and apoA-I protect against deep vein thrombosis in mice.
OBJECTIVE
Deep vein thrombosis (DVT) and pulmonary embolism are frequent causes of morbidity and mortality. The goal of our study was to determine whether plasma high-density lipoprotein (HDL), which inversely correlates with the risk of cardiovascular events, affects DVT.


RESULTS
Using a murine DVT model of inferior vena cava stenosis, we demonstrated that deficiency of the HDL receptor, scavenger receptor class B type I (SR-BI), promotes venous thrombosis. As SR-BI(-/-) mice have increased plasma cholesterol levels and abnormal HDL particles, we tested SR-BI(-/-) mice with an SR-BI liver transgene that normalizes both parameters. These mice also exhibited increased susceptibility to DVT, indicating a protective role of extrahepatic SR-BI. Mice lacking the major HDL apolipoprotein apoA-I or endothelial nitric oxide synthase (eNOS) (a downstream target of endothelial SR-BI signaling) also had a prothrombotic phenotype. Intravenous infusion of human apoA-I, an HDL component and SR-BI ligend, prevented DVT in wild-type but not SR-BI(-/-) or eNOS(-/-) mice, suggesting that its effect is mediated by SR-BI and eNOS. Intravenous apoA-I infusion abolished histamine-induced platelet-endothelial interactions, which are important for DVT initiation.


CONCLUSIONS
An apoA-I (HDL)-SR-BI-eNOS axis is highly protective in DVT and may provide new targets for prophylaxis and treatment of venous thrombosis.
Immune Disease Institute, Children’s Hospital Boston, Boston, MA 02115, USA.
Alexander
A
Brill
Ayce
A
Yesilaltay
Simon F
SF
De Meyer
Janka
J
Kisucka
Tobias A
TA
Fuchs
Olivier
O
Kocher
Monty
M
Krieger
Denisa D
DD
Wagner
D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001777:Blood Coagulation; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D051122:Scavenger Receptors, Class B / Q000502:physiology*; D020246:Venous Thrombosis / Q000517:prevention & control*
D016632:Apolipoprotein A-I; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse