Platelets Express Activated P2Y12 Receptor in Patients with Diabetes
Background—Platelets from patients with diabetes are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes. However, the underlying mechanism of hyperactivated platelets is not completely understood.
Methods—We measured P2Y12 expression on platelets from patients with type 2 diabetes mellitus (T2DM) and on platelets from rats with diabetes. We also assayed platelet P2Y12 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 NFκB pathway in regulating P2Y12 receptor expression in megakaryocytes.
Results—Platelet P2Y12 levels are 4-fold higher in patients with T2DM compared to healthy subjects. P2Y12 expression correlates with ADP-induced platelet aggregation (r = 0.89, P < 0.01). P2Y12 in platelets from patients with diabetes is constitutively activated. Though both AR-C78511, a potent P2Y12 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% vs 49 ± 5%, respectively, P < 0.05). Using a FeCl3-injury mesenteric arteriole thrombosis model in rats and an A-V shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on diabetic GK rats than cangrelor (thrombus weight 4.9 ± 0.3 mg vs 8.3 ± 0.4 mg, respectively, P < 0.01). We also found that a pathway involving high glucose-ROS-NFκB increases platelet P2Y12 receptor expression in diabetes.
Conclusions—Platelet P2Y12 receptor expression is significantly increased and the receptor is constitutively activated in T2DM patients, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in T2DM.
- inverse agonist
- diabetes mellitus
- cardiovascular disease
- P2Y12 receptor
- Received December 18, 2016.
- Revision received May 23, 2017.
- Accepted June 12, 2017.