P2Y12高表达在糖尿病心血管并发症中的作用及反向激动剂的防治作用

Cardiovascular complications, particularly coronary artery disease, are the leading cause of morbidity and mortality in diabetes patients, antiplatelet therapy is crucial to treat the cardiovascular complications in diabetes patients. Platelets of diabetes patients are characterized by increased reactivity, which contributes to not only the the increased prevalence of cardiovascular complications in diabetes patients, but also the inadequate response to currently available antiplatelet agents compared with non-diabetes patients. The mechanism underlying the increased platelet reactivity is still not completely understand, and the discovery of novel antiplatelet agents has been actively pursued to overcome the limitations of current antiplatelet agents. Our preliminary studies have shown that type 2 diabetes mellitus (T2DM) patients have dramatically enhanced platelet P2Y12 receptor expression, consistent with the reported P2Y12 signaling pathway upregulation. Based on two-state model of recetor activation theory and our previous work (Ding et al, Mol Pharmacol 2006; Zhang et al, J Thromb Haemost 2012), we hypothesize that P2Y12 receptors in T2DM patients are constitutively activated, and P2Y12 receptor inverse agonists have superior antiplatelet efficacy over neutral P2Y12 receptor antagonists. We will first investigate the constitutive activity of of the overexpressed P2Y12 receptors using platelets from T2DM patients and diabetes mice. Second, we will investigate the superior antiplatelet activity of AR-C78511, a potent P2Y12 receptor inverse agonist we reported previously, using platelets from T2DM patients and diabetes mice. Finally, we will investigate whether the increased P2Y12 expression increases thrombosis in diabetes mice and the in vivo antithrombotic effects of AR-C78511. These studies will shed novel insight into the pathogenesis of diabetes cardiovascular complications. It will also provide pivotal information for the use of P2Y12 receptor inverse agonist as novel antiplatelet agent for the prevention and treatment of cardiovascular complication in diabetes patients.

心血管并发症是糖尿病首位死亡原因，病人血小板反应性增高，原因仍不很清楚,现有抗血小板药效果欠佳。我们以往的研究发现P2Y12自发激活增加血小板反应性、血栓形成，P2Y12受体反向激动剂AR-C78511具有更好的抗血小板活性。我们最近发现II型糖尿病人血小板P2Y12表达明显升高，结合受体激活的二态模型理论，我们提出糖尿病时高表达的P2Y12受体存在自发激活，致血小板反应性增高，AR-C78511具有更好的抗血小板作用。拟用糖尿病人和糖尿病小鼠血小板研究高表达的P2Y12的自发激活活性、其与血小板高反应性的关系、AR-C78511更好的抗血小板活性，同时利用糖尿病小鼠模型，研究血小板P2Y12高表达与血栓形成的关系及 AR-C78511更好的抗血栓作用。本项目将进一步明确糖尿病心血管并发症的发病机制，为P2Y12受体反向激动剂作为新型抗血小板药更好地防治糖尿病心血管并发症提供重要理论依据。

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。.我们的研究发现，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。而与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。利用高糖培养的Meg-1细胞，我们证实了在糖尿病病人血小板、糖尿病大鼠模型的发现。研究还发现，高糖-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。.这一研究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，在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的同时，也为新型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抗血小板药物治疗提供了新思路和新方向。

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