Immune Disease Institute, Children’s Hospital Boston, Boston, MA 02115, USA.
Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1841-7. doi: 10.1161/ATVBAHA.112.252130. Epub 2012 May 31.
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.
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.
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.
深静脉血栓形成（DVT）和肺栓塞是发病率和死亡率的常见原因。我们的研究目的是确定与心血管事件风险呈负相关的血浆高密度脂蛋白（HDL）是否会影响 DVT。
我们使用下腔静脉狭窄的小鼠 DVT 模型，证明了 HDL 受体（清道夫受体 B 类 I，SR-BI）的缺乏会促进静脉血栓形成。由于 SR-BI(-/-) 小鼠的血浆胆固醇水平升高且 HDL 颗粒异常，我们测试了具有 SR-BI 肝转基因的 SR-BI(-/-) 小鼠，该转基因可使这两个参数正常化。这些小鼠也表现出对 DVT 的易感性增加，表明肝外 SR-BI 具有保护作用。缺乏主要的 HDL 载脂蛋白 apoA-I 或内皮型一氧化氮合酶（eNOS）（内皮 SR-BI 信号的下游靶标）的小鼠也具有促血栓形成表型。静脉内输注人 apoA-I，一种 HDL 成分和 SR-BI 配体，可预防野生型小鼠但不能预防 SR-BI(-/-)或 eNOS(-/-)小鼠的 DVT，表明其作用是通过 SR-BI 和 eNOS 介导的。静脉内 apoA-I 输注可消除组胺诱导的血小板-内皮相互作用，这对于 DVT 的启动很重要。
apoA-I（HDL）-SR-BI-eNOS 轴在 DVT 中具有高度保护作用，可能为预防和治疗静脉血栓形成提供新的靶标。
