Preconditioning improves coronary patency

项目总结 预适应(PC)是一种广为人知的现象，即短暂的心肌缺血发作 使心肌细胞对后来持续的缺血性损伤具有抵抗力。然而，来自我们小组的证据 已证明PC在维持血管通畅性方面具有辅助的、有利的作用。 反复血栓形成与急性缺血综合征的临床相似。我们假设，在我们的 以前的应用：(1)PC缺血所见的增强的通畅性是由于PC诱导的 血小板活化-聚集的一个或多个分子指标的减弱；以及(2)腺苷释放 在PC刺激期间，以及由此产生的对血小板表面腺苷A2a受体的刺激， 是提高通畅性的导火索。第一个概念得到了一个新的证据的支持 PC诱导的血小板P-选择素表达、血小板-纤维蛋白原结合显著下调，以及 中性粒细胞-血小板聚集体(NPA)的形成。然而，这种有利的分子指数衰减 并不能完全用血小板-A2a受体的刺激来解释。因此，我们的目标是 这一竞争性更新是对血小板-A2a受体范例的扩展，并研究 PC缺血引起的血管通畅性改善是多种因素相互作用的结果 多个触发物(即腺苷和缓激肽)作用于多个部位(中性粒细胞上的受体以及 血小板)。我们将使用生理和分子细胞端点的综合分析，在多个 反复血栓形成的活体模型(从大鼠到转基因小鼠再到狗)， 询问两个主要假设：(I)中性粒细胞(即NPA的形成和中性粒细胞的激活L- 选择素)在血栓复发的病理生理学中起作用。此外，腺苷在体内的释放 PC缺血通过A2A介导的降压有助于改善血管通畅性。 调节中性粒细胞L-选择素的激活。(Ii)PC缺血时缓激肽的释放及其迅速 稳定的缓激肽代谢产物的分解和产生，有助于PC诱导的增强 通过刺激血小板PAR4受体实现动脉通畅。此外，我们还提出，有利的 先期PC缺血的影响并不局限于一种预处理策略；而是：(Iii)基于PC 在复发血栓形成发生后应用的治疗方法，改善了我们的急性心肌梗死模型的动脉通畅性。 冠脉综合征。我们建议的最终目标是获得新的机械性见解，这些见解可能在 未来，将被用于为有发生血栓事件风险的患者设计新的治疗方法。

PROJECT SUMMARY Preconditioning (PC) is the well-described phenomenon whereby brief episodes of myocardial ischemia render cardiomyocytes resistant to a later, sustained ischemic insult. However, evidence from our group has shown that PC has an ancillary, favorable effect on the maintenance of vessel patency in models of recurrent thrombosis mimicking clinical instances of acute ischemic syndromes. We hypothesized, in our previous application, that: (1) the enhanced patency seen with PC ischemia is due to a PC-induced attenuation in one or more molecular indices of platelet activation-aggregation; and (2) adenosine liberated during the PC stimulus, and resultant stimulation of adenosine A2A receptors on the platelets' surface, serves as the trigger for the improved patency. The first concept was supported by novel evidence of a significant, PC-induced down-regulation of platelet P-selectin expression, platelet-fibrinogen binding, and formation of neutrophil-platelet aggregates (NPAs). However, this favorable attenuation in molecular indices of platelet reactivity was not explained solely by platelet-A2A receptor stimulation. Accordingly, our aim in this competitive renewal is to expand on the platelet-A2A receptor paradigm and investigate the concept that the improved vessel patency initiated by PC ischemia is a consequence of a complex interplay among multiple triggers (i.e., adenosine and bradykinin) acting at multiple sites (receptors on neutrophils as well as platelets). We will use an an integrated analysis of physiologic and molecular-cellular endpoints, in multiple in vivo models of recurrent thrombosis (ranging from rats to genetically modified mice to dogs), to interrogate two primary hypotheses: (I) Neutrophils (i.e., formation of NPAs and activation of neutrophil L- selectin) contribute to the pathophysiology of recurrent thrombosis. Moreover, release of adenosine during PC ischemia contributes to the improved maintenance of vessel patency by an A2A-mediated down- regulation of neutrophil L-selectin activation. (II) Release of bradykinin during PC ischemia, and its rapid breakdown and production of stable bradykinin metabolites, contribute to the PC-induced augmentation of arterial patency via stimulation of platelet PAR4 receptors. Furthermore, we propose that the favorable effects of antecedent PC ischemia are not confined to a pretreatment strategy; rather: (III) 'PC'-based therapies, applied after the onset of recurrent thrombosis, improve arterial patency in our models of acute coronary syndromes. The ultimate goal of our proposal is to obtain novel mechanistic insights that may, in future, be exploited for the design of new treatments for patients at risk of developing thrombotic events.