A specific CD36-dependent signaling pathway is required for platelet activation by oxidized low-density lipoprotein
A specific CD36-dependent signaling pathway is required for platelet activation by oxidized low-density lipoprotein
复制标题
DOI：
10.1161/circresaha.108.172064
复制
发表时间：
2008-06-20
影响因子：
20.1
通讯作者：
Silverstein, Roy L.
中科院分区：
文献类型：
--
作者：
Chen, Kan;Febbraio, Maria;Silverstein, Roy L.
与高脂血症相关的血小板过度活跃可能导致血栓前状态的发展。我们之前表明，在高脂血症和动脉粥样硬化的情况下形成氧化低密度脂蛋白（oxLDL），以CD36依赖性方式激活血小板。我们现在表明，在暴露于 oxLDL 的血小板中，丝裂原激活蛋白激酶 c-Jun N 末端激酶 (JNK) 2 及其上游激活剂 MKK4 被磷酸化。使用apoE(-/-)小鼠作为高脂血症模型，我们发现JNK以CD36依赖性方式在血小板中组成型磷酸化。抑制 src 激酶活性可减少 oxLDL 对 JNK 的磷酸化。免疫沉淀显示，在暴露于 oxLDL 的血小板中，活性磷酸化形式的 src 激酶 Fyn 和 Lyn 被募集至 CD36。体外，对有丝分裂原激活蛋白激酶 JNK 或 src 家族激酶进行药理学抑制，可消除 oxLDL 对血小板的激活作用。使用小鼠颈动脉血栓形成模型，我们证明了血栓内血小板 JNK 的 CD36 依赖性磷酸化。此外，JNK 的药理学抑制可延长野生型小鼠体内的血栓形成时间，但不会延长 cd36-null 小鼠的体内血栓形成时间。这些发现表明，oxLDL 激活血小板需要特定的 CD36 依赖性信号通路，并且可能为开发与动脉粥样硬化血栓形成比与正常止血更相关的新型抗血小板疗法提供见解。
Platelet hyperactivity associated with hyperlipidemia may contribute to development of a prothrombotic state. We previously showed that oxidized low-density lipoprotein (oxLDL) formed in the setting of hyperlipidemia and atherosclerosis activated platelets in a CD36-dependent manner. We now show that mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) 2 and its upstream activator MKK4 were phosphorylated in platelets exposed to oxLDL. Using apoE(-/-) mice as a model of hyperlipidemia, we showed that JNK was constitutively phosphorylated in platelets in a CD36-dependent manner. Inhibition of src kinase activity reduced JNK phosphorylation by oxLDL. Immunoprecipitations revealed that active phosphorylated forms of src kinases Fyn and Lyn were recruited to CD36 in platelets exposed to oxLDL. Pharmacological inhibition of the mitogen-activated protein kinase JNK or src family kinases abolished platelet activation by oxLDL in vitro. Using a murine carotid artery thrombosis model we demonstrated CD36-dependent phosphorylation of platelet JNK within thrombi. Furthermore, pharmacological inhibition of JNK prolonged thrombosis times in wild-type but not cd36-null mice in vivo. These findings suggest that a specific CD36-dependent signaling pathway is required for platelet activation by oxLDL and may provide insights related to development of novel antiplatelet therapies more relevant to atherothrombosis than to normal hemostasis.