Role of redox-sensitive signalling pathways linked to GPIIb-IIIa in platelet hyperactivity and thrombosis in diabetes

糖尿病已成为21世纪世纪的主要卫生保健挑战之一，并且是全球心血管疾病的主要原因。高达70%的糖尿病相关死亡是由于心血管疾病，主要与动脉粥样硬化血栓形成有关。糖尿病会加剧大动脉的动脉粥样硬化过程，增加急性心肌梗死、缺血性中风和外周疾病的风险。除了发展更广泛的动脉粥样硬化之外，糖尿病个体还表现出促血栓形成表型，其表现为血小板在斑块破裂部位的过度积聚。然而，糖尿病引起血小板活性亢进和血栓形成前表型的机制仍不完全清楚。杰克逊实验室（主办机构）最近定义了一种促进动脉血栓形成的新机制，涉及生物力学（流变学依赖性）血小板活化，导致盘状血小板聚集。初步数据表明，这种聚集机制在糖尿病中失调，导致体内过度的盘状血小板聚集和血栓形成。 氧化应激似乎通过改变主要血小板粘附受体αIIbβ3（通常称为GPIIb-IIIa）的剪切敏感性，在糖尿病中放大盘状血小板聚集中起关键作用。该项目的假设是，这种生物力学促血栓形成机制与GPIIb-IIIa相关的氧化还原敏感信号通路的改变有关。重要的是，过度的血小板聚集不能被常规抗血小板药物如阿司匹林和氯吡格雷抑制，这可能部分解释了糖尿病患者抗血栓治疗的疗效降低。 本提案的具体目的是研究抑制血小板氧化还原敏感性信号通路是否能减少糖尿病患者的血小板过度活跃和血栓形成。为了解决这个问题，将通过几种体外方法研究与GPIIb-IIIa激活相关的几种信号传导抑制剂对糖尿病血小板剪切依赖性粘附的功能影响。将使用几种血栓形成小鼠模型检查在体外高度有效的药理学抑制剂在体内抑制剪切依赖性盘状血小板聚集的能力。该项目的结果可能有助于确定降低糖尿病血栓前功能的全新方法。

Diabetes has become one of the major healthcare challenges of the 21st century and a leading cause of cardiovascular disease worldwide. Up to 70% of all diabetes-related deaths are due to cardiovascular disease, primary related to atherothrombosis. Diabetes enhances the atherosclerotic process in large arteries, increasing the risk of acute myocardial infarction, ischemic stroke and peripheral disease. In addition to developing more extensive atherosclerosis, diabetic individuals also exhibit a prothrombotic phenotype that manifest as an exaggerated accumulation of platelets at sites of plaque disruption. However, the mechanisms by which diabetes causes platelet hyperactivity and a prothrombotic phenotype remain incompletely understood. The Jackson laboratory (host institute) recently defined a new mechanism promoting arterial thrombus formation that involves biomechanical (rheology-dependent) platelet activation that leads to aggregation of discoid platelets. Preliminary data show evidence that this aggregation mechanism is dysregulated in diabetes, leading to excessive discoid platelet aggregation and thrombus formation in vivo. Oxidative stress seems to have a key role in amplifying discoid platelet aggregation in diabetes by altering the shear-sensitivity of the major platelet adhesion receptor αIIbβ3 (commonly referred to as GPIIb-IIIa). The hypothesis of this project is that this biomechanical prothrombotic mechanism is associated with alterations in redox-sensitive signal pathways linked to GPIIb-IIIa. Importantly, exaggerated platelet aggregation is not inhibited by conventional antiplatelet agents such as aspirin and clopidogrel, which may partly explain reduced efficacy of antithrombotic therapy in individual with diabetes. The specific aim in this proposal is to examine whether inhibiting platelet redox-sensitive signalling pathways reduces platelet hyperactivity and thrombosis in diabetes. To address the question the functional impact of several signalling inhibitors linked to GPIIb-IIIa activation on shear-dependent adhesion of diabetic platelets will be investigated by several in vitro approaches. Pharmacological inhibitors that are highly effective in vitro, will be examined for their ability to inhibit shear-dependent discoid platelet aggregation in vivo, using several thrombosis mouse models. Results of this project could help to identify entirely new approaches to reduce the prothrombotic function of diabetes.