Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivo
Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivo
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DOI：
10.1084/jem.20090687
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发表时间：
2009-10-26
影响因子：
15.3
通讯作者：
Gresele, Paolo
中科院分区：
文献类型：
--
作者：
Momi, Stefania;Falcinelli, Emanuela;Gresele, Paolo
血管损伤部位的血小板活化对于止血至关重要;然而，动脉损伤部位的过度血小板活化可导致不必要的动脉血栓形成，诱发急性心肌梗死或缺血性卒中。当促进血栓生长和稳定的物质积聚时，可能会发生超出止血目的的血小板活化。人血小板含有基质金属蛋白酶2（MMP-2），并在活化时释放它。活性MMP-2通过增强磷脂酰肌醇3-激酶活化来放大血小板对几种激动剂的聚集反应。使用几种体内血栓形成模型，我们表明，MMP-2基因的失活防止血栓形成诱导的弱，但不强，刺激小鼠，但只产生适度延长出血时间。此外，使用交叉输血实验和野生型/MMP-2（-/-）嵌合小鼠，我们表明，它是血小板衍生的MMP-2，促进血栓形成。最后，我们表明，血小板激活的轻度血管损伤诱导血栓形成在下游动脉损伤部位释放MMP-2。因此，血小板衍生的MMP-2通过放大血小板对弱活化刺激的反应在血栓形成中起关键作用。这些发现为开发MMP-2抑制剂预防血栓形成提供了新的可能性。
Platelet activation at a site of vascular injury is essential for the arrest of bleeding; however, excessive platelet activation at a site of arterial damage can result in the unwarranted formation of arterial thrombi, precipitating acute myocardial infarction, or ischemic stroke. Activation of platelets beyond the purpose of hemostasis may occur when substances facilitating thrombus growth and stability accumulate. Human platelets contain matrix metalloproteinase 2 (MMP-2) and release it upon activation. Active MMP-2 amplifies the platelet aggregation response to several agonists by potentiating phosphatidylinositol 3-kinase activation. Using several in vivo thrombosis models, we show that the inactivation of the MMP-2 gene prevented thrombosis induced by weak, but not strong, stimuli in mice but produced only a moderate prolongation of the bleeding time. Moreover, using cross-transfusion experiments and wild-type/MMP-2(-/-) chimeric mice, we show that it is platelet-derived MMP-2 that facilitates thrombus formation. Finally, we show that platelets activated by a mild vascular damage induce thrombus formation at a downstream arterial injury site by releasing MMP-2. Thus, platelet-derived MMP-2 plays a crucial role in thrombus formation by amplifying the response of platelets to weak activating stimuli. These findings open new possibilities for the prevention of thrombosis by the development of MMP-2 inhibitors.