Effect of oxidation on the platelet-activating properties of low-density lipoprotein
Effect of oxidation on the platelet-activating properties of low-density lipoprotein
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DOI：
10.1161/01.atv.0000158381.02640.4b
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发表时间：
2005-04-01
影响因子：
8.7
通讯作者：
Akkerman, JWN
中科院分区：
文献类型：
--
作者：
Korporaal, SJA;Gorter, G;Akkerman, JWN
由于氧化过程和低密度脂蛋白（LDL）的氧化易感性存在很大差异，并且缺乏LDL氧化的量化，氧化在LDL -血小板接触中的作用仍然难以捉摸。本研究旨在比较天然低密度脂蛋白（nLDL）和氧化低密度脂蛋白（oxLDL）的血小板活化情况。方法和结果-分离后，将nLDL与FeSO4进行透析，得到被氧化程度在0%至60%之间的LDL。对oxLDL制剂的血小板活化特性进行了表征。LDL氧化的增加通过2个独立的途径增强血小板活化，1个通过p38（MAPK）磷酸化，1个通过Ca2+动员。在0%和15%氧化之间，p38MAPK途径增强了凝血酶受体（PAR-1）激活肽（TRAP）诱导的纤维蛋白原结合，并且通过Ca2+的信号通路缺失。在> 30%氧化时，p38（MAPK）信号进一步增加，并伴有Ca2+动员和血小板聚集，在缺乏第二激动剂的情况下。尽管p38MAPK信号增加，但与TRAP的协同作用消失，oxLDL成为纤维蛋白原结合的抑制剂。抑制伴随着oxLDL与清道夫受体CD36的结合，CD36与纤维蛋白原受体α (IIb) β相关(3)。结论-在> 30%氧化时，LDL干扰配体与整合素α (IIb) β的结合(3)，从而减弱血小板功能。
Objective - Because of the large variation in oxidizing procedures and susceptibility to oxidation of low-density lipoprotein (LDL) and the lack in quantification of LDL oxidation, the role of oxidation in LDL - platelet contact has remained elusive. This study aims to compare platelet activation by native LDL (nLDL) and oxidized LDL (oxLDL).Methods and Results - After isolation, nLDL was dialyzed against FeSO4 to obtain LDL oxidized to well-defined extents varying between 0% and > 60%. The oxLDL preparations were characterized with respect to their platelet-activating properties. An increase in LDL oxidation enhances platelet activation via 2 independent pathways, 1 signaling via p38(MAPK) phosphorylation and 1 via Ca2+ mobilization. Between 0% and 15% oxidation, the p38MAPK route enhances fibrinogen binding induced by thrombin receptor ( PAR-1)- activating peptide ( TRAP), and signaling via Ca2+ is absent. At > 30% oxidation, p38(MAPK) signaling increases further and is accompanied by Ca2+ mobilization and platelet aggregation in the absence of a second agonist. Despite the increase in p38MAPK signaling, synergism with TRAP disappears and oxLDL becomes an inhibitor of fibrinogen binding. Inhibition is accompanied by binding of oxLDL to the scavenger receptor CD36, which is associated with the fibrinogen receptor, alpha(IIb)beta(3).Conclusion - At > 30% oxidation, LDL interferes with ligand binding to integrin alpha(IIb)beta(3), thereby attenuating platelet functions.