Preconditioning Improves Coronary Patency

预适应（PC）是一种描述良好的现象，即短暂的心肌缺血发作使心肌细胞对后来持续的缺血损伤具有抵抗力。然而，我们小组的证据表明，在模拟急性缺血性综合征临床实例的复发性血栓模型中，PC对维持血管通畅有辅助的有利作用。在之前的研究中，我们假设：(1)PC缺血导致的血管通畅增强是由于PC诱导的血小板激活-聚集的一个或多个分子指标的衰减；(2)在PC刺激过程中释放的腺苷，以及由此产生的血小板表面腺苷A2受体的刺激，是改善通畅的触发因素。第一个概念得到了新证据的支持，即pc诱导血小板p选择素表达下调，血小板-纤维蛋白原结合下调，中性粒细胞血小板聚集物（NPAs）形成。然而，血小板反应性分子指标的这种有利衰减并不能完全由血小板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，并研究由PC缺血引发的血管开放改善是多个触发因素（即腺苷和缓激素）在多个位点（中性粒细胞和血小板上的受体）之间复杂相互作用的结果。提出了两种假设：(1)中性粒细胞（即npa的形成和中性粒细胞l -选择素的激活）参与复发性血栓形成的病理生理机制。此外，PC缺血时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缺血时缓激肽的释放及其快速分解和稳定缓激肽代谢物的产生，通过刺激血小板PAR4受体，有助于PC诱导动脉通畅的增强。这些假设将通过在多种体内复发性血栓模型（从狗到大鼠，再到转基因小鼠）中对生理和分子细胞终点（即动脉通畅与最先进的血小板和中性粒细胞激活流式细胞术定量相一致）进行综合分析来验证。由此产生的机制见解可能最终在未来设计用于复发性血栓临床治疗的新疗法中被利用。

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.