Preconditioning improves coronary patency

项目摘要 预适应（PC）是一种被广泛描述的现象， 使心肌细胞对随后的持续缺血性损伤具有抵抗力。然而，我们小组的证据表明， 已经表明，PC对维持模型中血管通畅性具有辅助的有利作用， 类似急性缺血综合征的复发性血栓形成。我们假设，在我们的 之前的应用表明：（1）PC缺血时观察到的通畅性增强是由于PC诱导的 血小板活化-聚集的一个或多个分子指标减弱;和（2）腺苷释放 在PC刺激期间，以及血小板表面上腺苷A2 A受体的最终刺激， 作为提高开放性的触发器。第一个概念得到了新证据的支持， PC诱导的血小板P-选择素表达、血小板-纤维蛋白原结合和 嗜中性粒细胞-血小板聚集体（NPA）的形成。然而，分子指数的这种有利衰减 血小板A2 A受体刺激不能解释血小板反应性的增加。因此，我们的目标是， 这种竞争性更新是对血小板-A2 A受体范例的扩展，并研究了 PC缺血引起的血管通畅性改善是以下因素之间复杂相互作用的结果： 多个触发器（即，腺苷和缓激肽）作用于多个位点（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终点的综合分析， 复发性血栓形成的体内模型（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L- 选择素）有助于复发性血栓形成的病理生理学。此外，腺苷的释放在 PC缺血有助于通过A2 A介导的血管开放性降低来改善血管开放性的维持。 调节中性粒细胞L-选择素活化。(II)PC缺血时缓激肽的释放及其快速变化 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PAR 4受体实现动脉通畅。此外，我们建议， 先前PC缺血的影响不限于预处理策略;相反：（III）基于“PC”的 在我们的急性血栓形成模型中，在复发性血栓形成发作后应用的治疗可改善动脉通畅性。 冠状动脉综合征我们的建议的最终目标是获得新的机械见解， 未来，可用于设计新的治疗方法，用于有发生血栓事件风险的患者。

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.