Early platelet activation by low density lipoprotein via p38MAP kinase
Early platelet activation by low density lipoprotein via p38MAP kinase
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DOI：
10.1055/s-0037-1614909
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发表时间：
1999-12-01
影响因子：
6.7
通讯作者：
Akkerman, JWN
中科院分区：
文献类型：
--
作者：
Hackeng, CM;Relou, IAM;Akkerman, JWN
已知低密度脂蛋白（LDL）会使血小板对生理激动剂敏感。为了阐明这种致敏的基础，我们研究了p38（MAP）激酶（p38（MAPK））的参与。由于P38（MAPK）的Thr（180）和Tyr（182）上的双重磷酸化是激酶活化的触发因素，因此用识别双重磷酸化序列的抗体测量p38（MAPK）活性。LDL诱导p38（MAPK）的快速和剂量依赖性激活。Th激活不受多种血小板信号传导抑制剂的抑制，包括TxA（2）形成、磷脂酶C激活、Ca 2+动员和ERK 1/2激活。当蛋白激酶C被抑制时，只观察到p38（MAPK）激活的轻微减少。p38（MAPK）的激活被cAMP的升高强烈抑制。因此，p38（MAPK）-激活是大多数信号通路的上游，并接近LDL受体。使用抗体筛选了许多血小板受体。整合素α（IIb）β（3）和α（2）β（1）以及Fc γ RII受体、CD 36（血小板糖蛋白IV）、CD 68（gp 110）和低密度脂蛋白受体相关蛋白（LRP）与LDL诱导的p38（MAPK）激活无关。通过修饰载脂蛋白B100赖氨酸抑制LDL结合，使p38（MAPK）活化降低80%。p38（MAPK）的激活导致花生四烯酸（血栓烷A（2）合成的前体）的释放增加。总之，p38（MAPK）的激活可能是LDL致敏血小板的第一步，导致花生四烯酸代谢产物的形成和增加的聚集和分泌反应的生理激动剂。
Low Density Lipoprotein (LDL) is known to sensitize platelets for physiological agonists. To clarify the basis of this sensitization, we investigated the involvement of p38(MAP) Kinase(p38(MAPK)). As dual phosphorylation on Thr(180) and Tyr(182) of P38(MAPK) is the trigger for activation of the kinase, p38(MAPK)-activity was measured with an antibody that recognizes the dual-phosphorylated sequence. LDL induced a rapid and dose dependent activation of p38(MAPK). Th, activation was not inhibited by a wide variety of inhibitors of platelet signalling, including TxA(2)-formation, Phospholipase C-activation, Ca2+-mobilization and ERK 1/2-activation. Only a slight reduction in p38(MAPK)-activation was observed when protein kinase C was inhibited. Activation of p38(MAPK) was strongly inhibited by a rise in cAMP. Thus, p38(MAPK)-activation was upstream of most signalling pathways and close to the LDL-receptor. A number of platelet receptors was screened with the use of antibodies. Integrins alpha(IIb)beta(3) and alpha(2)beta(1), as well as the Fc gamma RII-receptor, CD36 (platelet glycoprotein IV), CD68 (gp110) and Low Density Lipoprotein-receptor related protein (LRP) were not implicated in LDL-induced p38(MAPK)-activation. Inhibition of LDL binding by modification of apo B100 lysines reduced p38(MAPK)-activation by 80 %. Activation of p38(MAPK) resulted in an increase in release of arachidonic acid, the precursor for thromboxane A(2) synthesis. In conclusion, activation of p38(MAPK) might be the first step in platelet sensitization by LDL, leading to formation of arachidonate metabolites and increased aggregation and secretion responses to physiological agonists.