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Platelets Express Activated P2Y 12 Receptor in Patients With Diabetes Mellitus
- Source :
- Circulation. 136:817-833
- Publication Year :
- 2017
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2017.
-
Abstract
- Background: Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. Methods: We measured P2Y 12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y 12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-κB pathway in regulating P2Y 12 receptor expression in megakaryocytes. Results Platelet P2Y 12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y 12 expression correlates with ADP-induced platelet aggregation (r=0.89, P 12 in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y 12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36±3% versus 49±5%, respectively, P 3 -injury mesenteric arteriole thrombosis model in rats and an arteriovenous shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on GK rats with diabetes mellitus than cangrelor (thrombus weight 4.9±0.3 mg versus 8.3±0.4 mg, respectively, P 12 receptor expression in diabetes mellitus. Conclusions Platelet P2Y 12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
business.industry
Type 2 Diabetes Mellitus
030204 cardiovascular system & hematology
medicine.disease
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
P2Y12
Endocrinology
Cangrelor
chemistry
Physiology (medical)
Diabetes mellitus
Internal medicine
Antithrombotic
Medicine
Inverse agonist
Platelet
Cardiology and Cardiovascular Medicine
business
Receptor
Subjects
Details
- ISSN :
- 15244539 and 00097322
- Volume :
- 136
- Database :
- OpenAIRE
- Journal :
- Circulation
- Accession number :
- edsair.doi...........56becb5a69b85c50a5ded1aa20db2f98