In vitro glycoxidized low-density lipoproteins and low-density lipoproteins isolated from type 2 diabetic patients activate platelets via p38 mitogen-activated protein kinase.
BACKGROUND
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 A(2), and the concentration of thromboxane B(2), the stable catabolite of the proaggregatory arachidonic acid metabolite thromboxane A(2), were assessed.


RESULTS
First, in vitro-glycoxidized LDLs increased the phosphorylation of platelet p38 MAPK as well as the concentration of thromboxane B(2). Second, LDLs isolated from plasma of poorly controlled type 2 diabetic patients stimulated both platelet p38 MAPK phosphorylation and thromboxane B(2) production and possessed high levels of malondialdehyde but normal alpha-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.
Calzada
Catherine
C
INSERM, UMR 870/Institut National des Sciences Appliquées de Lyon, F-69008 Lyon, France. catherine.calzada@insa-lyon.fr
Coulon
Laurent
L
Halimi
Déborah
D
Le Coquil
Elodie
E
Pruneta-Deloche
Valérie
V
Moulin
Philippe
P
Ponsin
Gabriel
G
Véricel
Evelyne
E
Lagarde
Michel
M
D001786:Blood Glucose / Q000378:metabolism*; D001792:Blood Platelets / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D010084:Oxidation-Reduction; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects*; D013929:Thromboxane B2 / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D001786:Blood Glucose; D006023:Glycoproteins; D008077:Lipoproteins, LDL; D008315:Malondialdehyde; D013929:Thromboxane B2; D048051:p38 Mitogen-Activated Protein Kinases