Methylglyoxal induces platelet hyperaggregation and reduces thrombus stability by activating PKC and inhibiting PI3K/Akt pathway

• Published in: PloS one Vol. 8; no. 9; p. e74401
• Main Authors: Hadas, Karin, Randriamboavonjy, Voahanginirina, Elgheznawy, Amro, Mann, Alexander, Fleming, Ingrid
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.09.2013; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Adhesion tests; Adult; Age; Agglomeration; AKT protein; Animals; Antibiotics; Blood clots; Blood platelets; Blood Platelets - drug effects; Blood Platelets - enzymology; Blood Platelets - pathology; Calcium (intracellular); Calcium - metabolism; Carotid artery; Cell Degranulation - drug effects; Cell Membrane - drug effects; Cell Membrane - enzymology; Collagen; Collagen - pharmacology; Development and progression; Diabetes; Diabetes mellitus; Diabetics; Enzyme Activation - drug effects; Fasting; Female; Fibronectin; Fibronectins; Glucose; Homeostasis; Humans; Hyperglycemia; Immunoglobulins; In vivo methods and tests; Insulin; Integrin beta3 - metabolism; Integrins; Kinases; Laboratory animals; Male; Medicine; Mice; Mice, Inbred C57BL; Myosin Light Chains - metabolism; Patients; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Platelet Adhesiveness - drug effects; Platelet aggregation; Platelet Aggregation - drug effects; Platelets; Protein kinase C; Protein Kinase C - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Pyruvaldehyde; Pyruvaldehyde - pharmacology; Signal transduction; Signaling; Stability; Thrombin; Thrombin - pharmacology; Thrombosis; Thrombosis - enzymology; Thrombosis - pathology; Type 2 diabetes; Vascular diseases; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0074401

Diabetes is characterized by a dysregulation of glucose homeostasis and platelets from patients with diabetes are known to be hyper-reactive and contribute to the accelerated development of vascular diseases. Since many of the deleterious effects of glucose have been attributed to its metabolite methylgyloxal (MG) rather than to hyperglycemia itself, the aim of the present study was to characterize the effects of MG on platelet function. Washed human platelets were pre-incubated for 15 min with MG and platelet aggregation, adhesion on matrix-coated slides and signaling (Western blot) were assessed ex vivo. In vivo, the effect of MG on thrombus formation was determined using the FeCl3-induced carotid artery injury model. MG potentiated thrombin-induced platelet aggregation and dense granule release, but inhibited platelet spreading on fibronectin and collagen. In vivo, MG accelerated thrombus formation but decreased thrombus stability. At the molecular level, MG increased intracellular Ca(2+) and activated classical PKCs at the same time as inhibiting PI3K/Akt and the β3-integrin outside-in signaling. In conclusion, these findings indicate that the enhanced MG concentration measured in diabetic patients can directly contribute to the platelet dysfunction associated with diabetes characterized by hyperaggregability and reduced thrombus stability.