Advanced glycation end products strongly activate platelets

Gawlowski, Thomas; Stratmann, Bernd; Ruetter, Ruth; Buenting, Christina; Menart, Barbara; Weiß, Jürgen; Vlassara, Helen; Koschinsky, Theodor; Tschöepe, Diethelm

doi:10.1007/s00394-009-0038-6

Cited by 48 publications

(36 citation statements)

References 31 publications

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“…However, though the effects of high levels of total plasma NEFAs have been studied (10,11,61), the putative deterioration in the NEFA binding capacity of albumin was not addressed in a systematic way. In previous studies, it was reported that oxidative stress and glycation caused conformational changes in albumin structure (14,29,62) with possible effects in vitro on platelet function (17,63,64). The novelty of the current study is the demonstration that glycation probably impairs the binding properties of albumin of patients with T2D.…”

Section: Discussionmentioning

confidence: 75%

“…The nonenzymatic covalent attachment of glucose molecules to protein and the subsequent free radical-mediated oxidation give rise to advanced glycoxidation end (AGE) products, of which methylglyoxal (MGO) is considered a key component through the Amadori rearrangement (15). Several reports indicate that AGE products are able at least in vitro to induce activation of various cells including platelets (16,17). In addition to classical glycemic indices, several recent reports indicated that glycated albumin is a relevant and practical biomarker for the progression of diabetic atherosclerosis (18)(19)(20).…”

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confidence: 99%

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Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

et al. 2014

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High plasma concentrations of nonesterified fatty acids (NEFAs), transported bound to serum albumin, are associated with type 2 diabetes (T2D). The effects of albumin on platelet function were investigated in vitro. Modifications of albumin, such as those due to glycoxidation, were found in patients with T2D, and the consequences of these modifications on biological mechanisms related to NEFA handling were investigated. Mass spectrometry profiles of albumin from patients with T2D differed from those from healthy control subjects. Diabetic albumin showed impaired NEFA binding capacity, and both structural and functional alterations could be reproduced in vitro by incubating native albumin with glucose and methylglyoxal. Platelets incubated with albumin isolated from patients with T2D aggregated approximately twice as much as platelets incubated with albumin isolated from healthy control subjects. Accordingly, platelets incubated with modified albumin produced significantly higher amounts of arachidonate metabolites than did platelets incubated with control albumin. We concluded that higher amounts of free arachidonate are made available for the generation of active metabolites in platelets when the NEFA binding capacity of albumin is blunted by glycoxidation. This newly described mechanism, in addition to hypoalbuminemia, may contribute to platelet hyperactivity and increased thrombosis, known to occur in patients with T2D.

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Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

et al. 2014

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“…Extracellular MRP-8/14 is then able to bind to receptors on target cells, including CD36 (8), RAGE (10), TLR4 (9), special carboxylated N-glycans (43), and heparin-like glycoaminoglycans (44). Interestingly, both CD36 (22) and RAGE (23) signaling have been directly implicated in platelet activation and thrombosis. Platelets also express functional levels of TLR4 (24), which may contribute to thrombocytopenia through neutrophil-dependent pulmonary sequestration in response to LPS (45).…”

Section: Discussionmentioning

confidence: 99%

“…Putative receptors for MRP-8/14 on target cells include CD36 (8), RAGE (10), and TLR4 (9). Interestingly, both CD36 (22) and RAGE (23) signaling have been directly implicated in platelet activation and thrombosis. Platelets also express functional levels of toll-like…”

Section: Role Of Intracellular Versus Extracellular Mrp-8/14 In Thrommentioning

confidence: 99%

Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis

et al. 2014

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Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14 -/-mice. We observed that MRP-14 and MRP-8/ MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14 -/-mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14 -/-mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14-dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.

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“…"Advanced glycation end products" (AGEs) induzieren eine leukozytäre Apoptose und eine Expression von Mac-1, die eine Plättchen-Leukozyten-Aggregation bewirken [40]. AGEs stimulieren die Expression von Rezeptoren für AGEs (RAGE) auf der Plättchenoberfläche [41].…”

Section: Plättchenaktivierung Bei Diabetes Mellitusunclassified

Die Rolle der Thrombozyten bei Atherosklerose, Diabetes mellitus und chronischer Niereninsuffizienz

Maurin

2010

Med Klin

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Erythropoiesis-stimulating agents (ESA) are used to treat renal anemia. The TREAT study (Trial to Reduce Cardiovascular Events with Aranesp Ther- apy) of diabetic patients with chronic kidney disease (CKD) found that the risk of stroke was significantly higher than in the control arm. This raises the question as to what causes this phenomenon. Platelets may play a crucial role in this context. Atherogenesis involves complex interactions between platelets and monocytes (platelet-monocyte crosstalk) and with endothelial cells. Platelets are activated in cases of diabetes mellitus, especially. During atherogenesis, partial functions of platelets other than those inhibited by aspirin, as a cyclooxygenase inhibitor, or by adenosine diphosphate receptor P2Y(12)antagonists, such as thienopyridines, are of relevance. During platelet-monocyte crosstalk, specifically, an important role is played by adhesion receptors such as selectins and integrins. In addition, ESA cause platelet activation by direct and indirect mechanisms. Antagonistic thereto is a renal bleeding tendency in cases of severe CKD, due to platelet dysfunction, which can be remedied with appropriate renal replacement therapy and administration of ESA in order to reach a hemoglobin (Hb) level of 10 g/dl. However, if the Hb level exceeds 10 g/dl, the even stronger platelet activation caused by ESA, combined with the activation caused by diabetes, leads to a prothrombotic state, which in patients with severe atherosclerosis can result in acute atherothrombotic complications, in the genesis of which platelets play a key role. This would be one hypothesis for explaining the increased incidence of strokes in the TREAT study.

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Advanced glycation end products strongly activate platelets

Cited by 48 publications

References 31 publications

Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis

Die Rolle der Thrombozyten bei Atherosklerose, Diabetes mellitus und chronischer Niereninsuffizienz

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