Published online before print May 22, 2008, doi: 10.1161/CIRCRESAHA.108.172064
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Submitted on January 28, 2008
Revised on May 13, 2008
Accepted on May 14, 2008
A Specific CD36-Dependent Signaling Pathway Is Required for Platelet Activation by Oxidized Low-Density Lipoprotein
Kan Chen ;
From the Program in Cell Biology (K.C., M.F., R.L.S.), Case Western Reserve University, and Department of Cell Biology (M.F., W.L., R.L.S.), Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
* To whom correspondence should be addressed. E-mail: silverr2{at}ccf.org.
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 that 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.
Key words: CD36 • JNK • thrombosis • hyperlipidemia
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