Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis
Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis
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DOI：
10.1074/jbc.m807820200
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发表时间：
2009-03-13
影响因子：
4.8
通讯作者：
Smyth, Susan S.
中科院分区：
文献类型：
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作者：
Pamuklar, Zehra;Federico, Lorenzo;Smyth, Susan S.
脂质介体溶血磷脂酸（LPA）是体外血管细胞功能的有效调节剂，但其在心血管系统中的生理作用在很大程度上未被探索。为了阐明LPA在调节血小板功能和血栓形成中的作用，我们研究了LPA对分离的小鼠血小板的作用。虽然LPA激活血小板从大多数人的捐助者，我们发现，处理分离的小鼠血小板与生理浓度的LPA衰减激动剂诱导的聚集。自分泌运动因子/溶血磷脂酶D（Enpp 2）的转基因过表达，其是在血浆中产生大量生物活性LPA所必需的酶，升高循环LPA水平并诱导小鼠的出血素质和血栓形成的减弱。血管内给予外源性LPA概括了在Enpp 2-Tg小鼠中观察到的出血时间延长。具有与50%正常血浆LPA水平相似的Enpp 2（+/-）小鼠更易于血栓形成。血浆自分泌运动因子在血小板聚集过程中与血小板相关，并在动脉血栓中浓缩，活化但非静息血小板以整合素依赖性方式结合重组自分泌运动因子/lysoPLD。这些结果确定了一种新的途径，其中LPA生产的autotaxin/lysoPLD调节小鼠止血和血栓形成，并表明，结合autotaxin/lysoPLD活化血小板可能提供一种机制，本地化LPA生产。
The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2(+/-) mice, which have similar to 50% normal plasma LPA levels, were more prone to thrombosis. Plasma autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.