title: Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36.
abstract: Diabetes mellitus has been associated with platelet hyperreactivity, which plays a central role in the hyperglycemia-related prothrombotic phenotype. The mechanisms responsible for this phenomenon are not established. In the present study, we investigated the role of CD36, a class-B scavenger receptor, in this process. Using both in vitro and in vivo mouse models, we demonstrated direct and specific interactions of platelet CD36 with advanced glycation end products (AGEs) generated under hyperglycemic conditions. AGEs bound to platelet CD36 in a specific and dose-dependent manner, and binding was inhibited by the high-affinity CD36 ligand NO(2)LDL. Cd36-null platelets did not bind AGE. Using diet- and drug-induced mouse models of diabetes, we have shown that cd36-null mice had a delayed time to the formation of occlusive thrombi compared with wild-type (WT) in a FeCl(3)-induced carotid artery injury model. Cd36-null mice had a similar level of hyperglycemia and a similar level of plasma AGEs compared with WT mice under this condition, but WT mice had more AGEs incorporated into thrombi. Mechanistic studies revealed that CD36-dependent JNK2 activation is involved in this prothrombotic pathway. Therefore, the results of the present study couple vascular complications in diabetes mellitus with AGE-CD36-mediated platelet signaling and hyperreactivity.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Weifei
authors.initials: W
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
mesh_terms: D000818:Animals; D058070:Asymptomatic Diseases; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000235:genetics / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004036:Diet, Atherogenic; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*; D006943:Hyperglycemia / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010974:Platelet Aggregation / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D013311:Streptozocin; D013927:Thrombosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: D018955:CD36 Antigens; D017127:Glycation End Products, Advanced; D013311:Streptozocin