Preconditioning improves coronary patency

预处理可改善冠状动脉通畅性

• 批准号: 7907571
• 负责人: KARIN PRZYKLENK
• 金额: $ 34.2万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907571
• 关键词: Acute; Adenosine; Adenosine A2A Receptor; Adhesions; Agonist; Animal Model; Aspirin; Binding; Blood Platelets; Bradykinin; Canis familiaris; Cardiac Myocytes; Clinical; Complex; Coronary; Dissociation; Down-Regulation; Event; Failure; Fibrinogen; Functional disorder; Funding; Future; Goals; Hospitalization; Infarction; Ischemia; Ischemic Preconditioning; L-Selectin; Laboratories; Maintenance; Mediating; Modeling; Molecular; Mus; Muscle Cells; Myocardial Ischemia; Neutrophil Activation; P-Selectin; PAWR gene; Patients; Physiological; Platelet Activation; Probability; Procedures; Production; Rattus; Recurrence; Reperfusion Therapy; Resistance; Risk; Role; Seminal; Site; Stimulus; Surface; Syndrome; Testing; Thrombosis; acute coronary syndrome; attenuation; base; clopidogrel; coronary perfusion; design; improved; in vivo Model; indexing; insight; molecular marker; mortality; neutrophil; novel; preconditioning; prophylactic; public health relevance; receptor; research study; treatment strategy

DESCRIPTION (provided by applicant): 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 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. PUBLIC HEALTH RELEVANCE: In patients with acute ischemic syndromes, failure to maintain coronary patency can precipitate multiple deleterious consequences, including prolonged hospitalization, an increased need for interventional procedures, and, most notably, a ~2-fold increase in mortality. Existing therapies aimed at reducing the probability of thrombotic events (most notably, prophylactic administration of aspirin and clopidogrel) are ineffective in an estimated 5-40% of patients. Thus, insights gained from the proposed experiments - i.e., identification of the mechanisms by which brief episodes of preconditioning ischemia and adenosine A2A receptor stimulation improve vessel patency - may, in future, be exploited in the design of novel anti-platelet strategies.

描述（由申请人提供）：预适应（PC）是一种被充分描述的现象，其中短暂的心肌缺血发作使心肌细胞对随后的、持续的缺血性损伤具有抵抗力。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 A2A 受体的刺激，充当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 A2A 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 A2A 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。我们将在多个复发性血栓形成体内模型（从大鼠到转基因小鼠再到狗）中对生理学和分子细胞终点进行综合分析，以检验两个主要假设：（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A2A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。此外，我们认为先前 PC 缺血的有利影响不仅限于预处理策略；相反：(III) 在复发性血栓形成发生后应用基于“PC”的疗法，可以改善我们的急性冠状动脉综合征模型中的动脉通畅性。我们提案的最终目标是获得新的机制见解，这些见解将来可能用于为有发生血栓事件风险的患者设计新的治疗方法。公共卫生相关性：对于患有急性缺血综合征的患者，未能维持冠状动脉通畅可能会引发多种有害后果，包括住院时间延长、介入手术的需求增加，最值得注意的是，死亡率增加约 2 倍。旨在降低血栓事件可能性的现有疗法（最值得注意的是，预防性服用阿司匹林和氯吡格雷）对估计 5-40% 的患者无效。因此，从所提出的实验中获得的见解，即确定短暂的预处理缺血和腺苷 A2A 受体刺激改善血管通畅的机制，将来可能会用于设计新型抗血小板策略。