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In Vitro Glycoxidized Low-Density Lipoproteins and Low-Density Lipoproteins Isolated from Type 2 Diabetic Patients Activate Platelets via p38 Mitogen-Activated Protein Kinase

Institut National de la Santé et de la Recherche Médicale, U870, F-69008 Lyon, France; Institut National des Sciences Appliquées de Lyon, Régulations Métaboliques, Nutrition, et Diabètes, F-69621 Villeurbanne, France; Institut National de la Recherche Agronomique, U1235, F-69008 Lyon, France; University of Lyon 1, F-69003 Lyon, France; and Hospices Civils de Lyon, F-69003 Lyon, France

Address all correspondence and requests for reprints to: Dr. Catherine Calzada, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 870/Institut National des Sciences Appliquées de Lyon, Régulations Métaboliques, Nutrition, et Diabètes/Institut Multidisciplinaire de Biochimie des Lipides, Bât. Louis Pasteur, 20 av. Albert Einstein, 69621 Villeurbanne, France. E-mail: catherine.calzada{at}insa-lyon.fr.

Context: Platelet hyperactivation contributes to the increased risk for atherothrombosis in type 2 diabetes and is associated with oxidative stress. Plasma low-density lipoproteins (LDLs) are exposed to both hyperglycemia and oxidative stress, and their role in platelet activation remains to be ascertained.

Objective: The aim of this study was to investigate the effects of LDLs modified by both glycation and oxidation in vitro or in vivo on platelet arachidonic acid signaling cascade. The activation of platelet p38 MAPK, the stress kinase responsible for the activation of cytosolic phospholipase A₂, and the concentration of thromboxane B₂, the stable catabolite of the proaggregatory arachidonic acid metabolite thromboxane A₂, were assessed.

Results: First, in vitro-glycoxidized LDLs increased the phosphorylation of platelet p38 MAPK as well as the concentration of thromboxane B₂. Second, LDLs isolated from plasma of poorly controlled type 2 diabetic patients stimulated both platelet p38 MAPK phosphorylation and thromboxane B₂ production and possessed high levels of malondialdehyde but normal -tocopherol concentrations. By contrast, LDLs from sex- and age-matched healthy volunteers had no activating effects on platelets.

Conclusions: Our results indicate that LDLs modified by glycoxidation may play an important contributing role in platelet hyperactivation observed in type 2 diabetes via activation of p38 MAPK.