A specific CD36-dependent signaling pathway is required for platelet activation by oxidized low-density lipoprotein.
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.
Chen
Kan
K
Program in Cell Biology, Case Western Reserve University, Cleveland, Ohio, USA.
Febbraio
Maria
M
Li
Wei
W
Silverstein
Roy L
RL
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D018955:CD36 Antigens / Q000235:genetics / Q000502:physiology*; D002341:Carotid Artery Thrombosis / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011833:Radiation Injuries, Experimental / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016037:Single-Blind Method; D013921:Thrombocytopenia / Q000097:blood / Q000209:etiology; D019061:src-Family Kinases / Q000502:physiology*
D001057:Apolipoproteins E; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D047428:Protein Kinase Inhibitors; C099252:oxidized low density lipoprotein; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse