Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion.
Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion.
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DOI：
10.1161/circulationaha.115.015656
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发表时间：
2015-07-07
期刊：
影响因子：
37.8
通讯作者：
Morrell CN
中科院分区：
文献类型：
--
作者：
Cameron SJ;Ture SK;Mickelsen D;Chakrabarti E;Modjeski KL;McNitt S;Seaberry M;Field DJ;Le NT;Abe J;Morrell CN
血小板在急性冠脉综合征(ACS)的缺血微血管环境中具有病理生理学作用。与正常健康状态下的血小板激活相比，疾病状态下的血小板激活机制受到的关注较少。在缺血和富含ROS的环境中，血小板的功能和激活机制可能与正常健康条件下不同。细胞外调节蛋白激酶5(ERK5)是一种丝裂原活化蛋白激酶(MAPK)家族成员，在低氧、富含ROS的环境中被激活，并响应受体信号转导机制。先前的研究表明ERK5对缺血后的内皮和心肌细胞具有保护作用。我们提出的证据表明，血小板表达ERK5，而血小板ERK5通过选择性受体依赖和受体非依赖性ROS介导的机制对缺血心肌中的血小板激活产生不利影响。使用分离的人血小板和小鼠心肌梗死(MI)模型，我们发现心肌梗死后血小板ERK5被激活，而血小板特异性ERK5−/−小鼠的血小板激活较少，MI体积缩小，心肌梗死后心功能改善。此外，心肌梗死后ERK5−/−血小板中ERK5下游调节蛋白的表达减少。ERK5在缺血条件下作为血小板激活剂发挥作用，而血小板ERK5在心肌梗死后维持某些血小板蛋白的表达，导致梗塞扩大。这表明正常健康状态下的血小板功能不同于慢性缺血和炎症状态下的血小板功能。在心肌梗死后血栓和炎症环境中，血小板ERK5可能是急性治疗干预的靶点。
Platelets have a pathophysiologic role in the ischemic microvascular environment of acute coronary syndromes (ACS). Compared to platelet activation in normal healthy conditions, less attention is given to mechanisms of platelet activation in diseased states. Platelet function and mechanisms of activation in ischemic and reactive oxygen species (ROS) rich environments may not be the same as in normal healthy conditions. Extracellular Regulated Protein Kinase 5 (ERK5) is a Mitogen Activated Protein Kinase (MAPK) family member activated in hypoxic, ROS rich environments, and in response to receptor signaling mechanisms. Prior studies suggest a protective effect of ERK5 in endothelial and myocardial cells following ischemia. We present evidence that platelets express ERK5 and platelet ERK5 has an adverse effect on platelet activation via selective receptor-dependent and receptor-independent ROS mediated mechanisms in ischemic myocardium. Using isolated human platelets and a mouse model of myocardial infarction (MI), we found that platelet ERK5 is activated post-MI and platelet specific ERK5−/− mice have less platelet activation, reduced MI size, and improved post-MI heart function. Furthermore, the expression of downstream ERK5 regulated proteins is reduced in ERK5−/− platelets post-MI. ERK5 functions as a platelet activator in ischemic conditions and platelet ERK5 maintains the expression of some platelet proteins following MI, leading to infarct expansion. This demonstrates that platelet function in normal healthy conditions is different from platelet function in chronic ischemic and inflammatory conditions. Platelet ERK5 may be a target for acute therapeutic intervention in the thrombotic and inflammatory post-MI environment.