Preconditioning Improves Coronary Patency

预处理可改善冠状动脉通畅性

• 批准号: 7581986
• 负责人: KARIN PRZYKLENK
• 金额: $ 30.44万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7581986
• 关键词: Acute; Adenosine; Adenosine A2 Receptors; Adhesions; Agonist; Animal Model; Arts; Aspirin; Binding; Biological Markers; Blood Platelets; Bradykinin; Canis familiaris; Cardiac Myocytes; Clinical; Clinical Treatment; Complex; Coronary; Dissociation; Down-Regulation; End Point; Event; Failure; Fibrinogen; Functional disorder; Funding; Future; Hospitalization; Infarction; Ischemia; Ischemic Preconditioning; L-Selectin; Laboratories; Maintenance; Mediating; Modeling; Molecular; Mus; Muscle Cells; Myocardial Ischemia; Neutrophil Activation; P-Selectin; PAWR gene; Patients; Personal Satisfaction; Physiological; Physiological reperfusion; Platelet Activation; Procedures; Production; Rattus; Recurrence; Reperfusion Therapy; Research Personnel; Resistance; Risk; Site; Stimulus; Surface; Syndrome; Testing; Thrombosis; acute coronary syndrome; attenuation; clopidogrel; concept; coronary perfusion; design; improved; in vivo Model; indexing; insight; mortality; neutrophil; novel; preconditioning; programs; prophylactic; receptor; size

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 A2 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 neutrophilplatelet aggregates (NPAs). However, this favorable attenuation in molecular indices of platelet reactivity was not explained solely by platelet-A2 receptor stimulation. Accordingly, our aim in this competitive renewal is to expand upon the platelet-A2 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). Two hypotheses are proposed: (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 A2-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. These hypotheses will be tested by an integrated analysis of physiologic and molecular-cellular endpoints (i.e., arterial patency in concert with state-of-the-art flow cytometric quantitation of platelet and neutrophil activation) in multiple in vivo models of recurrent thrombosis (from dogs, to rats, to genetically modified mice). The resulting mechanistic insights may, ultimately, be exploited in the future design of novel therapies for the clinical treatment of recurrent thrombosis.

预适应（PC）是一种被充分描述的现象，短暂的心肌缺血发作使心肌细胞对随后的持续缺血损伤产生抵抗力。然而，我们小组的证据表明，在模拟急性缺血综合征临床实例的复发性血栓形成模型中，PC 对维持血管通畅具有辅助、有利的作用。在我们之前的申请中，我们假设：（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数的减弱； (2) PC 刺激期间释放的腺苷以及由此产生的血小板表面腺苷 A2 受体的刺激，可作为改善通畅的触发因素。第一个概念得到了 PC 诱导的血小板 P-选择素表达、血小板纤维蛋白原结合和中性粒细胞血小板聚集体 (NPA) 形成显着下调的新证据的支持。然而，血小板反应性分子指数的这种有利减弱并不能仅仅通过血小板 A2 受体刺激来解释。因此，我们在这一竞争性更新中的目标是扩展血小板 A2 受体范式，并研究这样的概念：PC 缺血引起的血管通畅性改善是作用于多个位点（中性粒细胞和血小板上的受体）的多个触发因素（即腺苷和缓激肽）之间复杂相互作用的结果。提出了两个假设：(I) 中性粒细胞（即 NPA 的形成和中性粒细胞 L-选择素的激活）有助于复发性血栓形成的病理生理学。此外，PC 缺血期间腺苷的释放有助于通过 A2 介导的中性粒细胞 L-选择素激活的下调来改善血管通畅的维持。 (II) PC 缺血期间缓激肽的释放及其快速分解和稳定的缓激肽代谢物的产生，通过刺激血小板 PAR4 受体，有助于 PC 诱导的动脉通畅性增强。这些假设将通过在多种复发性血栓形成体内模型（从狗、大鼠到转基因小鼠）中对生理学和分子细胞终点（即动脉通畅性与血小板和中性粒细胞活化的最先进流式细胞术定量相结合）的综合分析进行检验。由此产生的机制见解最终可能会被用于未来临床治疗复发性血栓形成的新疗法的设计。