Platelet-Specific p38α Deficiency Improved Cardiac Function After Myocardial Infarction in Mice
Platelet-Specific p38α Deficiency Improved Cardiac Function After Myocardial Infarction in Mice
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血小板特异性 p38 α 缺乏改善小鼠心肌梗塞后的心脏功能
DOI：
10.1161/atvbaha.117.309856
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发表时间：
2017-01-01
影响因子：
8.7
通讯作者：
Liu, Junling
中科院分区：
文献类型：
--
作者：
Shi, Panlai;Zhang, Lin;Liu, Junling
丝裂原活化蛋白激酶（mitogen-activated protein kinases，MAPK），尤其是p38，在心肌梗死后心脏疾病和心脏重构中起着重要作用。然而，激活和功能的MAPK在体内冠状动脉血栓形成及其与临床outcomes.Approach和结果的关系仍然知之甚少，在这里，我们表明，p38 a是主要的同种型表达在人类和小鼠血小板。在左前降支动脉结扎模型中，血小板特异性p38 α缺陷小鼠表现出血栓形成和止血受损，但心功能改善，梗死面积缩小，炎症反应减少，微血栓形成。信号分析表明，p38激活是血小板受体激动剂或活性氧治疗后最早的事件之一。p38 α/MAPK活化蛋白激酶2/热休克蛋白27和p38 α/胞质磷脂酶A2是缺血环境中调节受体介导或过氧化氢诱导的血小板活化的主要途径。此外，ERK 1/2（细胞外信号调节激酶）在受体或活性氧诱导的p38介导的血小板活化中的不同作用反映了MAPK之间复杂的协同关系。临床样本分析显示，MAPKs在术前ST段抬高型心肌梗死患者的血小板中高度磷酸化，p38磷酸化水平升高与无复流结局相关。结论：我们得出结论，p38 α是血小板活化的关键调节因子，也是高度血栓性病变和无复流的潜在指标。抑制血小板p38a可以改善ST段抬高型心肌梗死患者的临床预后。
Objective-MAPKs (mitogen-activated protein kinases), especially p38, play detrimental roles in cardiac diseases and cardiac remodeling post-myocardial infarction. However, the activation and function of MAPKs in coronary thrombosis in vivo and its relationship with clinical outcomes remain poorly understood.Approach and Results-Here, we showed that p38a was the major isoform expressed in human and mouse platelets. Platelet-specific p38 alpha-deficient mice presented impaired thrombosis and hemostasis but had improved cardiac function, reduced infarct size, decreased inflammatory response, and microthrombus in a left anterior descending artery ligation model. Signaling analysis revealed that p38 activation was one of the earliest events in platelets after treatment with receptor agonists or reactive oxygen species. p38 alpha/MAPK-activated protein kinase 2/heat shock protein 27 and p38 alpha/cytosolic phospholipases A2 were the major pathways regulating receptor-mediated or hydrogen peroxide-induced platelet activation in an ischemic environment. Moreover, the distinct roles of ERK1/2 (extracellular signal-regulated kinase) in receptor-or reactive oxygen species-induced p38-mediated platelet activation reflected the complicated synergistic relationships among MAPKs. Analysis of clinical samples revealed that MAPKs were highly phosphorylated in platelets from preoperative patients with ST-segment-elevation myocardial infarction, and increased phosphorylation of p38 was associated with no-reflow outcomes.Conclusions-We conclude that p38 alpha serves as a critical regulator of platelet activation and potential indicator of highly thrombotic lesions and no-reflow, and inhibition of platelet p38a may improve clinical outcomes in subjects with ST-segment- elevation myocardial infarction.Visual Overview-An online visual overview is available for this article.