Extrahepatic High-Density Lipoprotein Receptor SR-BI and ApoA-I Protect Against Deep Vein Thrombosis in Mice
Extrahepatic High-Density Lipoprotein Receptor SR-BI and ApoA-I Protect Against Deep Vein Thrombosis in Mice
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DOI：
10.1161/atvbaha.112.252130
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发表时间：
2012-08-01
影响因子：
8.7
通讯作者：
Wagner, Denisa D.
中科院分区：
文献类型：
--
作者：
Brill, Alexander;Yesilaltay, Ayce;Wagner, Denisa D.
目的-深静脉血栓（DVT）和肺栓塞是发病和死亡的常见原因。我们研究的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。方法和结果 - 使用下腔静脉狭窄的小鼠 DVT 模型，我们证明 HDL 受体、B 型清道夫受体 I 型 (SR-BI) 的缺乏会促进静脉血栓形成。由于 SR-BI-/- 小鼠血浆胆固醇水平升高和异常 HDL 颗粒，我们测试了带有 SR-BI 肝脏转基因的 SR-BI-/- 小鼠，该转基因使这两个参数正常化。这些小鼠还表现出对 DVT 的易感性增加，表明肝外 SR-BI 的保护作用。缺乏主要 HDL 载脂蛋白 apoA-I 或内皮一氧化氮合酶 (eNOS)（内皮 SR-BI 信号传导的下游靶标）的小鼠也具有促血栓表型。静脉输注人 apoA-I（HDL 成分和 SR-BI 配体）可预防野生型小鼠的 DVT，但不能预防 SR-BI-/- 或 eNOS(-/-) 小鼠，表明其作用是由 SR-BI 和 eNOS 介导的。静脉输注apoA-I消除了组胺诱导的血小板-内皮相互作用，这对于DVT的发生很重要。结论-apoA-I（HDL）-SR-BI-eNOS轴在DVT中具有高度保护性，可能为预防和治疗静脉血栓形成提供新的靶点。 （动脉硬化血栓 Vasc Biol. 2012；32：1841-1848。）
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.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 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.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. (Arterioscler Thromb Vasc Biol. 2012;32:1841-1848.)