Oxidized high-density lipoprotein inhibits platelet activation and aggregation via scavenger receptor BI
Oxidized high-density lipoprotein inhibits platelet activation and aggregation via scavenger receptor BI
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DOI：
10.1182/blood-2007-08-107813
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Podrez, Eugene A.
中科院分区：
文献类型：
--
作者：
Valiyaveettil, Manojkumar;Kar, Niladri;Podrez, Eugene A.
已有大量研究报道动脉粥样硬化斑块内膜和血浆中存在氧化修饰的高密度脂蛋白，但其在血栓性疾病发病机制中的作用尚不明确。我们现在报道，OxHDL，而不是天然的高密度脂蛋白，是由生理性激动剂诱导的血小板激活和聚集的有效抑制物。这种抗血栓作用具有浓度和时间依赖性，并与脂蛋白氧化程度呈正相关。氧化脂蛋白是已知的清道夫受体B型、CD36和清道夫受体BI型(SR-BI)的配体，这两种受体都表达在血小板上。使用小鼠CD36(-/-)或SR-BI-/-血小板的研究表明，OxHDL的抗血栓活性依赖于血小板SR-BI，而不是CD36。由于人和小鼠血小板与抗SR-BI封闭抗体预先孵育可消除OxHDL的抑制作用，因此需要与SR-BI结合。对内皮型一氧化氮合酶(ENOS)(-/-)、Akt(-/-)和Akt-2(-/-)小鼠的激动剂诱导的血小板聚集有与野生型(WT)小鼠相同程度的抑制作用，表明OxHDL的作用是通过不同于eNOS/Akt途径的途径实现的。这些新的发现表明，与氧化型低密度脂蛋白(OxLDL)的血栓前活性相反，高密度脂蛋白在氧化时获得依赖于血小板SR-BI的抗血栓活性。
Numerous studies have reported the presence of oxidatively modified high-density lipoprotein (OxHDL) within the intima of atheromatous plaques as well as in plasma; however, its role in the pathogenesis of thrombotic disease is not established. We now report that OxHDL, but not native HDL, is a potent inhibitor of platelet activation and aggregation induced by physiologic agonists. This antithrombotic effect was concentration and time dependent and positively correlated with the degree of lipoprotein oxidation. Oxidized lipoproteins are known ligands for scavenger receptors type B, CD36 and scavenger receptor B type I (SR-BI), both of which are expressed on platelets. Studies using murine CD36(-/-) or SR-BI-/- platelets demonstrated that the antithrombotic activity of OxHDL depends on platelet SR-BI but not CD36. Binding to SR-BI was required since preincubation of human and murine platelets with anti-SR-BI blocking antibody abrogated the inhibitory effect of OxHDL. Agonist-induced aggregation of platelets from endothelial nitric oxide synthase (eNOS)(-/-), Akt(-/-), and Akt-2(-/-) mice was inhibited by OxHDL to the same degree as platelets from wild-type (WT) mice, indicating that the OxHDL effect is mediated by a pathway different from the eNOS/Akt pathway. These novel findings suggest that contrary to the prothrombotic activity of Oxidized low-density lipoprotein (OxLDL), HDL upon oxidation acquires antithrombotic activity that depends on platelet SR-BI.