Platelets Express Activated P2Y(12) Receptor in Patients With Diabetes Mellitus

doi:10.1161/CIRCULATIONAHA.116.026995

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Platelets Express Activated P2Y(12) Receptor in Patients With Diabetes Mellitus
	Hu, Liang 4,9; Chang, Lin 9; Zhang, Yan 9; Zhai, Lili 9; Zhang, Shenghui 2,9; Qi, Zhiyong 8; Yan, Hongmei 7; Yan, Yan 5; Luo, Xinping ; Zhang, Si 9
刊名	CIRCULATION
	2017-08-29
卷号	136 期号:9 页码:817-U102
关键词	antiplatelet antithrombotic AR-C78511 cangrelor inverse agonist P2Y(12) P2Y(12) receptor antagonist type 2 diabetes mellitus
ISSN号	0009-7322
DOI	10.1161/CIRCULATIONAHA.116.026995
文献子类	Article
英文摘要	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-kappa B 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<0.01). P2Y(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<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-kappa B increases platelet P2Y(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.
资助项目	National Natural Science of Foundation of China[81373411] ; National Natural Science of Foundation of China[81402920] ; National Natural Science of Foundation of China[81673429] ; Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning[00000000]
WOS关键词	NF-KAPPA-B ; INVERSE AGONISM ; METAPHYSEAL CHONDRODYSPLASIA ; MYOCARDIAL-INFARCTION ; CONSTITUTIVE ACTIVITY ; ANTIPLATELET THERAPY ; OXIDATIVE STRESS ; ARTERY-DISEASE ; HEART-DISEASE ; IN-VIVO
WOS研究方向	Cardiovascular System & Cardiology
语种	英语
出版者	LIPPINCOTT WILLIAMS & WILKINS
WOS记录号	WOS:000408418600005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272519]
专题	药理学第一研究室
通讯作者	Ding, Zhongren
作者单位	1.Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19122 USA; 2.Wenzhou Med Univ, Affiliated Hosp 1, Dept Hematol, Wenzhou Key Lab Hematol, Wenzhou, Peoples R China 3.Temple Univ, Sol Sherry Thrombosis Res Ctr, Philadelphia, PA 19122 USA; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol 1, Shanghai, Peoples R China; 5.Fudan Univ, Zhongshan Hosp, Div Cardiovasc Dis, Shanghai, Peoples R China; 6.Fudan Univ, Zhongshan Hosp, Dept Endocrinol & Metab, Shanghai, Peoples R China; 7.Fudan Univ, Huashan Hosp, Div Endocrinol & Metab, Shanghai, Peoples R China; 8.Fudan Univ, Huashan Hosp, Div Cardiovasc Dis, Shanghai, Peoples R China; 9.Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Minist Educ,Key Lab Metab & Mol Med, Shanghai, Peoples R China;
推荐引用方式 GB/T 7714	Hu, Liang,Chang, Lin,Zhang, Yan,et al. Platelets Express Activated P2Y(12) Receptor in Patients With Diabetes Mellitus[J]. CIRCULATION,2017,136(9):817-U102.
APA	Hu, Liang.,Chang, Lin.,Zhang, Yan.,Zhai, Lili.,Zhang, Shenghui.,...&Ding, Zhongren.(2017).Platelets Express Activated P2Y(12) Receptor in Patients With Diabetes Mellitus.CIRCULATION,136(9),817-U102.
MLA	Hu, Liang,et al."Platelets Express Activated P2Y(12) Receptor in Patients With Diabetes Mellitus".CIRCULATION 136.9(2017):817-U102.