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Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus
Liang Hu1, Lin Chang1, Yan Zhang1
1From Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China (L.H., L.C., Y.Z., L.Z., Shenghui Z., Si Z., Z.D.); Division of Cardiovascular Disease (Z.Q.), Division of Endocrinology and Metabolism (H.Y.), Huashan Hospital, Fudan University, Shanghai, China; Department of Endocrinology and Metabolism (H.Y.), Division of Cardiovascular Disease (Y.Y.), Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pharmacology I, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (L.H., Y.W.); Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.). Dr Shenghui Zhang is presently at Department of Hematology, Wenzhou Key Laboratory of Hematology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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 P2Y12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. 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 nuclear factor-κB pathway in regulating P2Y12 receptor expression in megakaryocytes.
Results:
Platelet P2Y12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y12 expression correlates with ADP-induced platelet aggregation (r=0.89, P<0.01). P2Y12 in platelets from patients with diabetes mellitus is constitutively activated. Although 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% versus 49±5%, respectively, P<0.05). Using a FeCl3-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<0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-κB increases platelet P2Y12 receptor expression in diabetes mellitus.
Conclusions:
Platelet P2Y12 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.
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