Platelets: Context-Dependent Vascular Protectors or Mediators of Disease.
Platelets: Context-Dependent Vascular Protectors or Mediators of Disease.
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DOI：
10.1161/atvbaha.115.305898
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Early Career Committee
中科院分区：
文献类型：
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作者：
Westrick R;Fredman G;Early Career Committee
E26动脉血栓形成VASc Biol 2015年7月已被证明前解介质可减少PLA的形成15、16，这可能是ASA阻止oxLDL刺激的PMA形成的机制之一。关于ASA或专门的调解如何阻止PLA的进一步机械性研究是有意义的。凝血酶通过蛋白水解酶激活受体激活血小板，是终末期闭塞性动脉粥样硬化血栓形成事件的主要参与者。Kuipers等人和van Montfoort等人的研究重点是使用超声动脉粥样硬化斑块破裂模型研究斑块破裂和血栓形成的远端事件。17这些研究集中在接触激活途径的蛋白水解酶因子XI和XII在闭塞性血栓形成中的作用。利用载脂蛋白E−/−小鼠模型，在动脉粥样硬化斑块破裂的背景下研究了Fx1和FxII缺乏。Van Montfoort等人证明了FXI在动脉粥样硬化性疾病中的重要性，他们证明了急性破裂的动脉粥样硬化斑块上的血栓形成依赖于FXI，并且通过反义寡核苷酸降低FXI的水平可以减少血栓的形成和血小板的聚集。18类似地，使用相同的斑块破裂模型，Kuijpers等人证明了另一种接触激活蛋白酶FXII通过使用2种FXII药物抑制剂来调节破裂斑块上血栓的形成过程。19这个小组还证明了FXII与固定的斑块匀浆结合。综上所述，这些研究表明，接触激活通路在动脉粥样硬化血栓形成的晚期事件中发挥着重要作用，因此可能是预防斑块破裂背景下闭塞性血栓形成的一个可行的治疗靶点。20靶向这些分子可能特别有吸引力，因为FXI和FXII缺陷与出血倾向增加无关。
e26 Arterioscler Thromb Vasc Biol July 2015 proresolving mediators have been shown to decrease PLA formation15, 16 and may be a mechanism underlying ASA’s ability to block oxLDL-stimulated PMA formation. Further mechanistic studies addressing how ASA or specialized proresolving mediators block PLAs are of interest. Platelets are activated by thrombin via the protease-activated receptors and are major players in the terminal occlusive arterial atherothrombotic event. Research by Kuipers et al and van Montfoort et al focused on the distal events of plaque rupture and thrombus development using an ultrasound atherosclerotic plaque rupture model. 17 These investigations centered on the contribution of the contact activation pathway proteases Factors XI and XII on occlusive thrombus formation. Using the ApoE−/− mouse model, FXI and FXII deficiency were investigated in the context of atherosclerotic plaque rupture. Van Montfoort et al demonstrated the importance of FXI in atherothrombotic disease by showing that the thrombus formation on an acutely ruptured atherosclerotic plaque is dependent on FXI and that thrombus development and platelet accumulation can be decreased by reducing FXI levels by antisense oligonucleotides. 18 Similarly, using the same plaque rupture model, Kuijpers et al demonstrated that another contact activation protease, FXII, regulates the process of thrombus formation on ruptured plaques through the use of 2 FXII pharmacological inhibitors. 19 This group also demonstrated that FXII binds to immobilized plaque homogenates. Taken together, these studies suggest that the contact activation pathway plays an important role in the late events of atherothrombosis and thus may be a viable therapeutic target for preventing occlusive thrombus formation in the context of plaque rupture. 20 Targeting these molecules may be especially attractive because FXI and FXII deficiencies are not associated with increased bleeding tendency.