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 hyperglycemiarelated 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 highaffinity CD36 ligand NO 2 LDL. Cd36-null platelets did not bind AGE. Using dietand 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 wildtype (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. IntroductionDiabetes mellitus (DM) is associated with an increased risk of pathologic arterial thrombosis, including myocardial infarction and stroke. [1][2][3] Factors underlying this risk include accelerated atherosclerosis, endothelial dysfunction, and platelet hyperreactivity, but the mechanisms linking diabetes to platelet hyperreactivity are not well understood. 4,5 We and others have shown that platelets express receptors, including scavenger receptors and TLRs, that recognize endogenous and exogenous "danger signals," the so-called dangerassociated molecular patterns (DAMPs). 6,7 We hypothesized that endogenous DAMPs that are generated in hyperlipidemia, diabetes, obesity, and other chronic inflammatory conditions could interact with platelets through these receptors to mediate platelet activation and induce a prothrombotic state. Indeed, in mouse models of hyperlipidemia and oxidant stress, we showed that oxidized LDL, a lipid-based DAMP, induced a prothrombotic state via interactions with the platelet type 2 scavenger receptor CD36. [8][9][10] Similarly, oxidized phospholipids on the surface of cell-derived microparticles were shown to interact with platelet CD36 and promote thrombosis after oxidant injury to the arterial wall. 11 Chronic hyperglycemia is a common feature of diabetes and is an important initiator of vascular complications, many of which have been related to vascular and inflammatory cell interactions with advanced glycation end products (AGEs). 12,13 These heterogeneous, long-lived protein adducts are produced from a nonenzymatic chemical reaction between sugars and the amino groups of proteins. 14 Circulating levels of AGEs, detected most common...

Oxidized LDL activates blood platelets through CD36/NOX2–mediated inhibition of the cGMP/protein kinase G signaling cascade

“…33,37 In contrast, endothelial-derived microparticles, advanced glycation end products, and MRP14 can drive thrombosis. [38][39][40] Platelet hyperactivity that underpins arterial thrombosis in the context of dyslipidemia is thought to proceed through the actions of oxLDL. 10,11,41 However, whereas the activation of platelets by different forms of oxLDL has been widely reported and occurs through a variety of mechanisms, it has been difficult to understand how oxLDL may act in vivo given its modest effects on platelet activation in vitro and ex vivo.…”

Extracellular Vesicles Activate a CD36-Dependent Signaling Pathway to Inhibit Microvascular Endothelial Cell Migration and Tube Formation

“…As a class B scavenger receptor on macrophages, it recognizes patterns presented on pathogens or pathogen infected cells to facilitate clearance by the phagocytic cells 4,6,7 . CD36 also binds endogenous danger signal ligands including modified lipids expressed on lipoproteins 8 and apoptotic cells 2,9 , advanced glycated proteins 10 , fibrillar β-amyloid protein 11 and S100A family pro-inflammatory peptides 12 . Recognition of a specific protein domain known as thrombospondin type I repeats (TSR) present in anti-angiogenic proteins like TSP-1, TSP-2 and brain angiogenesis inhibitor 1 (BAI-1) by CD36 on MVEC mediates anti-angiogenic signaling.…”

Emerging roles for platelets as immune and inflammatory cells

“…thrombosis, including TLR9 and CD36, but their role in inflammation and platelet immune cell interactions remains to be determined. [82][83][84] Monocytes and neutrophils are the most numerous innate immune cells in the blood. Monocytes have major roles in chronic cardiovascular diseases including atherosclerosis.…”