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Exposure of plasminogen and a novel plasminogen receptor, Plg-RKT, on activated human and murine platelets.

纤溶酶原和新型纤溶酶原受体Plg-RKT在活化的人和鼠血小板上的暴露。

  • 影响因子:7.27
  • DOI:10.1182/blood.2020007263
  • 作者列表:"Whyte CS","Morrow GB","Baik N","Booth NA","Jalal MM","Parmer RJ","Miles LA","Mutch NJ
  • 发表时间:2021-01-14
Abstract

:Plasminogen activation rates are enhanced by cell surface binding. We previously demonstrated that exogenous plasminogen binds to phosphatidylserine-exposing and spread platelets. Platelets contain plasminogen in their α-granules, but secretion of plasminogen from platelets has not been studied. Recently, a novel transmembrane lysine-dependent plasminogen receptor, Plg-RKT, has been described on macrophages. Here, we analyzed the pool of plasminogen in platelets and examined whether platelets express Plg-RKT. Plasminogen content of the supernatant of resting and collagen/thrombin-stimulated platelets was similar. Pretreatment with the lysine analog, ε-aminocaproic acid, significantly increased platelet-derived plasminogen (0.33 vs 0.08 nmol/108 platelets) in the stimulated supernatant, indicating a lysine-dependent mechanism of membrane retention. Lysine-dependent, platelet-derived plasminogen retention on thrombin and convulxin activated human platelets was confirmed by flow cytometry. Platelets initiated fibrinolytic activity in fluorescently labeled plasminogen-deficient clots and in turbidimetric clot lysis assays. A 17-kDa band, consistent with Plg-RKT, was detected in the platelet membrane fraction by western blotting. Confocal microscopy of stimulated platelets revealed Plg-RKT colocalized with platelet-derived plasminogen on the activated platelet membrane. Plasminogen exposure was significantly attenuated in thrombin- and convulxin-stimulated platelets from Plg-RKT-/- mice compared with Plg-RKT+/+ littermates. Membrane exposure of Plg-RKT was not dependent on plasminogen, as similar levels of the receptor were detected in plasminogen-/- platelets. These data highlight Plg-RKT as a novel plasminogen receptor in human and murine platelets. We show for the first time that platelet-derived plasminogen is retained on the activated platelet membrane and drives local fibrinolysis by enhancing cell surface-mediated plasminogen activation.

摘要

: 纤溶酶原激活速率通过细胞表面结合而增强。我们以前证明外源性纤溶酶原与磷脂酰丝氨酸接触和扩散的血小板结合。血小板在其 α-颗粒中含有纤溶酶原,但尚未研究从血小板分泌纤溶酶原。最近,在巨噬细胞上描述了一种新的跨膜赖氨酸依赖性纤溶酶原受体plg-rkt。在这里,我们分析了血小板中的纤溶酶原池,并检查了血小板是否表达plg-rkt。静息和胶原/凝血酶刺激的血小板的上清液的纤溶酶原含量是相似的。用赖氨酸类似物 ε-氨基己酸预处理显著增加刺激上清液中的血小板衍生纤溶酶原 (0.33对0.08 nmol/108血小板),表明赖氨酸依赖性膜保留机制。通过流式细胞术证实赖氨酸依赖性、血小板衍生的纤溶酶原在凝血酶和惊厥活化的人血小板上的保留。血小板在荧光标记的纤溶酶原缺乏凝块和浊度测定凝块溶解试验中引发纤维蛋白溶解活性。通过蛋白质印迹法在血小板膜组分中检测到与plg-rkt一致的17-kda条带。刺激的血小板共聚焦显微镜显示Plg-RKT与血小板衍生的纤溶酶原在活化的血小板膜上共定位。与plg-rkt +/+ 同窝小鼠相比,来自plg-rkt-/-小鼠的凝血酶和惊厥刺激的血小板中的纤溶酶原暴露显著减弱。Plg-rkt的膜暴露不依赖于纤溶酶原,因为在纤溶酶原-/-血小板中检测到类似水平的受体。这些数据强调Plg-RKT是人和鼠血小板中新的纤溶酶原受体。我们首次证明血小板衍生的纤溶酶原保留在活化的血小板膜上,并通过增强细胞表面介导的纤溶酶原激活来驱动局部纤维蛋白溶解。

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DOI:10.1007/s11033-021-06299-9
作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

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