Korporaal Suzanne J A, Van Eck Miranda, Adelmeijer Jelle, Ijsseldijk Martin, Out Ruud, Lisman Ton, Lenting Peter J, Van Berkel Theo J C, Akkerman Jan-Willem N
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, and Institute of Biomembranes, Utrecht University, The Netherlands.
Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2476-83. doi: 10.1161/ATVBAHA.107.150698. Epub 2007 Aug 30.
The interaction of platelets with low density lipoprotein (LDL) contributes to the development of cardiovascular disease. Platelets are activated by native LDL (nLDL) through apoE Receptor 2' (apoER2')-mediated signaling to p38(MAPK) and by oxidized LDL (oxLDL) through lysophosphatidic acid (LPA) signaling to Rho A and Ca2+. Here we report a new mechanism for platelet activation by oxLDL.
Oxidation of nLDL increases p38(MAPK) activation through a mechanism that is (1) independent of LPA, and (2) unlike nLDL-signaling not desensitized by prolonged platelet-LDL contact or inhibited by receptor-associated protein or chondroitinase ABC. Antibodies against scavenger receptors CD36 and SR-A alone fail to block p38(MAPK) activation by oxLDL but combined blockade inhibits p38(MAPK) by >40% and platelet adhesion to fibrinogen under flow by >60%. Mouse platelets deficient in either CD36 or SR-A show normal p38(MAPK) activation by oxLDL but combined deficiency of CD36 and SR-A disrupts oxLDL-induced activation of p38(MAPK) by >70%.
These findings reveal a novel platelet-activating pathway stimulated by oxLDL that is initiated by the combined action of CD36 and SR-A.
血小板与低密度脂蛋白（LDL）的相互作用促进心血管疾病的发展。天然LDL（nLDL）通过载脂蛋白E受体2'（apoER2'）介导的信号传导激活血小板至p38丝裂原活化蛋白激酶（p38(MAPK)），而氧化型LDL（oxLDL）通过溶血磷脂酸（LPA）信号传导激活血小板至Rho A和Ca2+。在此，我们报告oxLDL激活血小板的一种新机制。
nLDL的氧化通过以下机制增加p38(MAPK)的激活：（1）独立于LPA；（2）与nLDL信号传导不同，不会因血小板与LDL的长时间接触而脱敏，也不会被受体相关蛋白或软骨素酶ABC抑制。单独针对清道夫受体CD36和SR-A的抗体未能阻断oxLDL对p38(MAPK)的激活，但联合阻断可使p38(MAPK)的激活抑制>40%，并使流动状态下血小板与纤维蛋白原的黏附抑制>60%。缺乏CD36或SR-A的小鼠血小板对oxLDL表现出正常的p38(MAPK)激活，但CD36和SR-A的联合缺乏会使oxLDL诱导的p38(MAPK)激活破坏>70%。
这些发现揭示了一种由oxLDL刺激的新型血小板激活途径，该途径由CD36和SR-A的联合作用启动。
