复旦大学丁忠仁课题组发现糖尿病心血管并发症高发的新机制

来源:生物帮 发布时间:2017年07月11日 浏览次数: 【字体: 收藏 打印文章
2017年6月30日,国际心血管病顶级学术期刊《Circulation》发表复旦大学基础医学院丁忠仁课题组发现糖尿病心血管并发症高发的新机制。研究论文题为《糖尿病人血小板高表达自发激活P2Y12受体》(Platelets express activated P2Y12 receptor in patients with diabetes)。博士研究生胡亮为第一作者,丁忠仁研究员为通讯作者。
 
随着我国居民生活水平的不断提高以及人口老龄化程度的不断加深,目前我国11.6%的成年人患有糖尿病,占全球总糖尿病人数的25%左右,有50%以上的糖尿病患者死于心脑血管并发症。血小板异常激活作为中风、冠心病等动脉血栓性疾病的重要病理基础,也是糖尿病人常规服用抗血小板药物预防心脑血管并发症的重要原因。目前临床常用的阿司匹林、氯吡格雷等抗血小板药物对于部分糖尿病患者心脑血管并发症的治疗效果并不理想,存在阿司匹林抵抗、氯吡格雷抵抗现象,无法有效地减少心脑血管并发症的发生率。
 
丁忠仁课题组首次揭示了糖尿病人血小板P2Y12受体高表达、异常激活的现象、机制、反向激动剂的治疗学优势,不但为糖尿病高发心脑血管并发症的原因找到了一条新的重要线索,也为抗血小板药物的研发、糖尿病患者心脑血管并发症的个体化药物治疗提供了新思路和新方向。
 
研究发现糖尿病患者和糖尿病大鼠血小板上P2Y12受体表达显著增加、发生受体自发激活,在无激动剂结合的情况下向胞内传递受体激活信号,导致血小板异常激活、体内血栓形成增加;与2015年FDA新近审批上市的抗血小板新药坎格雷洛(cangrelor)相比,反向激动剂ARC-78511对于P2Y12受体高表达且自发激活的糖尿病人血小板有更好的抗血小板作用,对糖尿病大鼠具有更显著的抗血小板、抗血栓作用;ROS-NFκB信号通路激活是血小板P2Y12受体和多种炎症因子表达异常增加的幕后分子机制。本研究有助于推动新型抗血小板药物的研发,为氯吡格雷抵抗的患者的个体化药物治疗提供了重要的科学依据。
 
糖尿病血小板高反应性的新机制
 
原文摘要: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 P2Y12activation 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.
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