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. We would like to determine whether plasma high-density lipoprotein (HDL), which inversely correlates with the risk of cardiovascular events, affects DVT.
Methods and 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 ligand, 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.
Conclusion—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.
- deep vein thrombosis
- scavenger receptor class B type I
- apolipoprotein A-I
- high-density lipoprotein
- endothelial nitric oxide synthase
- Received December 1, 2011.
- Accepted May 11, 2012.
- © 2012 American Heart Association, Inc.