Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice
Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice
复制标题
血小板 MEKK3 调节小鼠动脉血栓形成和心肌梗塞扩张。
DOI：
10.1182/bloodadvances.2017015149
复制
发表时间：
2018-06-26
期刊：
影响因子：
7.5
通讯作者：
Liu, Junling
中科院分区：
文献类型：
--
作者：
Fan, Xuemei;Wang, Conghui;Liu, Junling
MAPKs在血小板活化中起重要作用。然而，MAPKs在血小板中调节的分子机制在很大程度上仍然未知。实时聚合酶链反应和蛋白质印迹数据显示，MEMO，一个关键的MAP 3 K家族成员，在人类和小鼠血小板中表达。然后，开发巨核细胞/血小板特异性MEKK 3缺失（MEKK 3（-/-））小鼠以阐明MEMO的血小板相关功能。我们发现，激动剂诱导的聚集和脱粒减少MEKK 3（-/-）血小板在体外。MEMO缺陷显著损害整合素α IIb β 3介导的由内而外信号传导，但不影响由外向内信号传导。在分子水平上，MEKK 3缺陷导致细胞外信号调节激酶1/2（ERK 1/2）和c-Jun NH 2-末端激酶2的激活严重受损，但不包括p38或ERK 5。在体内，MEKK 3（-/-）小鼠在FeCl 3诱导的颈动脉损伤后表现出延迟的血栓形成。有趣的是，MEKK 3（-/-）小鼠的尾部出血时间是正常的。此外，MEKK 3（-/-）小鼠具有更少的微血栓，减少心肌梗死（MI）的大小，并改善MI小鼠模型中MI后的心脏功能。提示MEMO在血小板MAPK活化中起重要作用，可能成为抗血栓形成和预防心肌梗死扩大的新靶点。
MAPKs play important roles in platelet activation. However, the molecular mechanisms by which MAPKs are regulated in platelets remain largely unknown. Real-time polymerase chain reaction and western blot data showed that MEMO, a key MAP3K family member, was expressed in human and mouse platelets. Then, megakaryocyte/platelet-specific MEKK3-deletion (MEKK3(-/-)) mice were developed to elucidate the platelet-related function(s) of MEMO. We found that agonist-induced aggregation and degranulation were reduced in MEKK3(-/-) platelets in vitro. MEMO deficiency significantly impaired integrin alpha IIb beta 3-mediated inside-out signaling but did not affect the outside-in signaling. At the molecular level, MEKK3 deficiency led to severely impaired activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun NH2-terminal kinase 2 but not p38 or ERK5. In vivo, MEKK3(-/-) mice showed delayed thrombus formation following FeCl3-induced carotid artery injury. Interestingly, the tail bleeding time was normal in MEKK3(-/-) mice. Moreover, MEKK3(-/-) mice had fewer microthrombi, reduced myocardial infarction (MI) size, and improved post-MI heart function in a mouse model of MI. These results suggest that MEMO plays important roles in platelet MAPK activation and may be used as a new effective target for antithrombosis and prevention of MI expansion.