A specific CD36-dependent signaling pathway is required for platelet activation by oxidized low-density lipoprotein. Circ Res 2008 Jun 20;102(12):1512-9
Date
05/24/2008Pubmed ID
18497330Pubmed Central ID
PMC2749986DOI
10.1161/CIRCRESAHA.108.172064Scopus ID
2-s2.0-48249139826 (requires institutional sign-in at Scopus site) 152 CitationsAbstract
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.
Author List
Chen K, Febbraio M, Li W, Silverstein RLAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApolipoproteins E
Atherosclerosis
Blood Platelets
CD36 Antigens
Carotid Artery Thrombosis
Humans
Hypercholesterolemia
JNK Mitogen-Activated Protein Kinases
Lipoproteins, LDL
MAP Kinase Kinase 4
MAP Kinase Signaling System
Male
Mice
Mice, Knockout
Phosphorylation
Platelet Activation
Protein Kinase Inhibitors
Protein Processing, Post-Translational
Radiation Injuries, Experimental
Signal Transduction
Single-Blind Method
Thrombocytopenia
src-Family Kinases
