Diabetic Patients Without Vascular Complications Display Enhanced Basal Platelet Activation and Decreased Antioxidant Status

Véricel, Evelyne; Januel, Caroline; Carreras, Marı́a Cecilia; Moulin, Philippe; Lagarde, Michel

doi:10.2337/diabetes.53.4.1046

Cited by 77 publications

(64 citation statements)

References 58 publications

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“…Activation of platelets represents a key event not only in acute thrombosis but also under chronic pathophysiological conditions such as diabetes, atherosclerosis, or aging, all of which are associated with alterations in the intracellular redox state [1,2]. Chronic activation of platelets results in an increased risk of capillary plugging as well as in an increased systemic vascular tone.…”

Section: Introductionmentioning

confidence: 99%

Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets

Schildknecht

Loo

Weber³

et al. 2008

Free Radical Biology and Medicine

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Endogenous peroxynitrite modulates PGHS-1-dependent thromboxane A2 formation and aggregation in human platelets Abstract Aggregation of activated platelets is considerably mediated by the autocrine action of thromboxane A2 (TxA2) which is formed in a prostaglandin endoperoxide H2 synthase-1 (PGHS-1 or COX-1)-dependent manner. The activity of PGHS-1 can be stimulated by peroxides, an effect termed "peroxide tone", that renders PGHS-1 the key regulatory enzyme in the formation of TxA2. Activated platelets release nitric oxide (*NO) and superoxide (O*2) but their interactions with the prostanoid pathway have been controversially discussed in platelet physiology and pathophysiology. The current study demonstrates that endogenously formed peroxynitrite at nanomolar concentrations, originating from the interaction of *NO and *O2, potently activated PGHS-1, which parallels TxA2 formation and aggregation in human platelets. Inhibition of the endogenous formation of either *NO or O*2 resulted in a concentration-dependent decline of PGHS-1 activity, TxA2 release, and aggregation. The concept of peroxynitrite as modulator of TxA2 formation and aggregation explains the interaction of *NO and O*2 with the PGHS pathway and suggests a mechanism by which antioxidants can regulate PGHS-1-dependent platelet aggregation. This may provide a molecular explanation for the clinically observed hyperreactivity of platelets in high-risk patients and serve as a basis for novel therapeutic interventions. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ÔØ Å ÒÙ× Ö ÔØ A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT

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Section: Introductionmentioning

confidence: 99%

Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets

Schildknecht

Loo

Weber³

et al. 2008

Free Radical Biology and Medicine

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“…Increased platelet activation occurs in type 2 diabetes [12] and the metabolic syndrome [13,14], and may represent a key contributing factor in the process of atherosclerosis and its thrombotic complications. Oxidative stress has been identified as one of the factors closely associated with platelet hyperactivation in diabetes [12] and lipid hydroperoxides have been shown to stimulate platelet aggregation [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…Oxidative stress has been identified as one of the factors closely associated with platelet hyperactivation in diabetes [12] and lipid hydroperoxides have been shown to stimulate platelet aggregation [15,16]. In vitro, moreover, oxidised LDL [17,18] and LDL from patients with type 1 [19] or type 2 diabetes [20] activated platelets via an increase of p38 mitogen-activated protein kinase (MAPK) phosphorylation and thromboxane B 2 (TxB 2 ) formation.…”

Section: Introductionmentioning

confidence: 99%

LDL from obese patients with the metabolic syndrome show increased lipid peroxidation and activate platelets

et al. 2011

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Aims/hypothesis This study assessed oxidative stress in LDL from obese patients with the metabolic syndrome and compared it with that in LDL from type 2 diabetic patients or control volunteers. It also determined the effect on platelets of LDL from the three groups. Methods The profiles of lipids, fatty acids and fatty acid oxidation products were determined in LDL isolated from plasma of patients with the metabolic syndrome, patients with type 2 diabetes and volunteers (n=10 per group). The effects of LDL from the participant groups on the platelet arachidonic acid signalling cascade and aggregation were investigated. Results Compared with LDL from control volunteers, LDL from obese metabolic syndrome and type 2 diabetic patients had lower cholesteryl ester, higher triacylglycerol and lower ethanolamine plasmalogen levels. Proportions of linoleic acid were decreased in phosphatidylcholine and cholesteryl esters in LDL from both patient groups. Among the markers of lipid peroxidation, oxidation products of linoleic acid (hydroxy-octadecadienoic acids) and malondialdehyde were increased by 59% and twofold, respectively in LDL from metabolic syndrome and type 2 diabetic patients. LDL from metabolic syndrome and type 2 diabetic patients were equally potent in activating the platelet arachidonic acid signalling cascade through increased phosphorylation of p38 mitogen-activated protein kinase and cytosolic phospholipase A 2 , and through increased thromboxane B 2 formation. LDL from patients with the metabolic syndrome and type 2 diabetes potentiated platelet aggregation by threefold and 3.5-fold respectively, whereas control LDL had no activating effects on platelets. Conclusions/interpretation The metabolic syndrome in obese patients, without or with diabetes, is associated with increased oxidative stress in LDL, which triggers platelet activation.

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“…In addition to these endothelium-confined factors, platelet dysfunction [7][8][9] and an imbalance of plasmatic coagulation factors further contribute to a prothrombotic state in the diabetic patient. In particular, augmented synthesis of factor VII, thrombin, tissue factor and PAI-1 is detected in the diabetic patient, while anticoagulative substances, such as thrombomodulin and protein C, are diminished [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

C-peptide exerts antithrombotic effects that are repressed by insulin in normal and diabetic mice

et al. 2006

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Aims/hypothesis: Diabetic macro-and microangiopathy are associated with a high risk of vascular complications. The diabetic patient exhibits a pathological coagulation state, with an increased synthesis of coagulation factors and plasminogen activator inhibitor 1 (PAI-1) as well as an enhanced aggregation of platelets. Previous studies have shown that C-peptide can reduce leucocyteendothelial cell interaction and improve microvascular blood flow in patients with type 1 diabetes. In the present study, we examined in vivo whether C-peptide is able to reduce platelet activation and through that microvascular thrombus formation. Materials and methods: In the microvessels of cremaster muscle preparations taken from normal and diabetic mice, ferric chloride-induced thrombus formation was analysed using intravital fluorescence microscopy. Results: I.V. administration of C-peptide in high dose (70 nmol/kg), but not in low dose (7 nmol/kg), caused a significant delay in arteriolar and venular thrombus growth in normal and diabetic mice. This effect was repressed by cremaster muscle superfusion with insulin (100 μU/ml) in diabetic animals, but particularly in normal animals. In parallel, immunohistochemistry demonstrated a higher number of PAI-1-expressing vessels in cremaster muscle tissue from control animals and from animals treated with C-peptide and insulin compared with tissue from animals with C-peptide treatment application alone. Conclusions/interpretation: We conclude that C-peptide possesses antithrombotic actions in vivo. A causal role of PAI-1 in this scenario needs to be further addressed. However, the reversal of C-peptide action by insulin may invalidate the use of this peptide as a treatment option to improve rheology and microcirculation in diabetic patients.

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Diabetic Patients Without Vascular Complications Display Enhanced Basal Platelet Activation and Decreased Antioxidant Status

Cited by 77 publications

References 58 publications

Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets

Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets

LDL from obese patients with the metabolic syndrome show increased lipid peroxidation and activate platelets

C-peptide exerts antithrombotic effects that are repressed by insulin in normal and diabetic mice

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