血小板在糖尿病患者中表达激活的 P2Y 受体。
Platelets Express Activated P2Y Receptor in Patients With Diabetes Mellitus.
机构信息
From 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.
出版信息
Circulation. 2017 Aug 29;136(9):817-833. doi: 10.1161/CIRCULATIONAHA.116.026995. Epub 2017 Jun 21.
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 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y 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 receptor expression in megakaryocytes.
RESULTS
Platelet P2Y levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y expression correlates with ADP-induced platelet aggregation (r=0.89, <0.01). P2Y in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y 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, <0.05). Using a FeCl-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, <0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-κB increases platelet P2Y receptor expression in diabetes mellitus.
CONCLUSIONS
Platelet P2Y 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.
背景
糖尿病患者的血小板活性增强。活性增强的血小板可能导致心血管并发症，并导致糖尿病患者对抗血小板药物的反应不足。然而，血小板活性增强的潜在机制尚未完全阐明。
方法
我们测量了 2 型糖尿病患者和糖尿病大鼠的血小板上 P2Y 的表达，并通过测量 cAMP 和 VASP 磷酸化来测定血小板 P2Y 的激活。比较了 AR-C78511 和坎格雷洛在大鼠中的抗血小板和抗血栓作用。最后，我们探讨了核因子-κB 通路在调节巨核细胞中 P2Y 受体表达中的作用。
结果
与健康受试者相比，2 型糖尿病患者的血小板 P2Y 水平高 4 倍。P2Y 表达与 ADP 诱导的血小板聚集呈正相关(r=0.89，<0.01)。糖尿病患者的血小板 P2Y 持续激活。尽管强效 P2Y 反向激动剂 AR-C78511 和坎格雷洛对健康受试者的血小板均具有相似的抗血小板作用，但 AR-C78511 对糖尿病患者的血小板的抗血小板作用强于坎格雷洛(聚集率分别为 36±3%和 49±5%，均<0.05)。在糖尿病 GK 大鼠的 FeCl 损伤肠系膜小动脉血栓形成模型和大鼠动静脉分流血栓形成模型中，我们发现反向激动剂 AR-C78511 比坎格雷洛具有更强的抗血栓作用(血栓重量分别为 4.9±0.3mg 和 8.3±0.4mg，均<0.01)。我们还发现，高糖反应性氧物质核因子-κB 通路增加了糖尿病中血小板 P2Y 受体的表达。
结论
2 型糖尿病患者的血小板 P2Y 受体表达显著增加，受体持续激活，导致血小板活性增强，并限制了 2 型糖尿病患者抗血小板药物的疗效。
Zotero 插件