Preconditioning Improves Coronary Patency

预处理可改善冠状动脉通畅性

• 批准号: 6733616
• 负责人: KARIN PRZYKLENK
• 金额: $ 27.83万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6733616
• 关键词: adenosine; angina pectoris; coronary occlusion /thrombosis; cytoprotection; dogs; fibrin; fibrinolysis; flow cytometry; hemostasis; human subject; myocardial ischemia /hypoxia; platelet aggregation; purinergic receptor; receptor binding; selectins

DESCRIPTION (provided by applicant): Evidence from our laboratory has revealed that brief episodes of antecedent 'preconditioning' ischemia, in addition to limiting infarct size: (1) improve coronary artery patency in a canine model of primary hemostasis mimicking unstable angina; and (2) enhance the speed and efficacy of thrombolysis in a canine model of coagulation and persistent thrombotic occlusion. Our results have further implicated release of adenosine from ischemic/reperfused myocardium, and subsequent stimulation of platelet adenosine A2 receptors, as playing a pivotal role in this phenomenon. However, the specific 'distal' molecular mechanisms responsible for these improvements in coronary patency are unknown. Platelet adhesion, activation -- and, ultimately, aggregation via the binding of fibrinogen to glycoprotein (GP) llb/lll receptors on adjacent platelets -- represents the underlying 'pathophysiology' of recurrent ischemia in the setting of unstable angina. Thus, our first hypothesis is that the improved coronary patency seen with brief antecedent ischemia/platelet A2 receptor stimulation is achieved by a down-regulation in the expression of adhesion molecules and/or ligands involved in the formation and stabilization of platelet aggregates -- specifically, GP IIb/IIIa, P-selectin, von Willebrand Factor, PECAM and/or GP Ib. The evolution from an unstable platelet 'plug' to a persistent, fibrin-containing clot involves the thrombin-catalyzed conversion of fibrinogen (the molecular 'bridge' in platelet aggregates) to fibrin, thrombin-mediated activation of Factor XIII and subsequent Factor XIII-catalyzed fibrin cross-linking. Accordingly, our second hypothesis is that brief antecedent ischemia/A2 receptor stimulation elicits -- as a consequence of changes in platelet activation/aggregation and adhesion molecule expression -- modifications in coagulation and thus fibrin polymerization during clot development that facilitate penetration and binding of the lytic agent and thus accelerate thrombolysis. These concepts will be tested via an integrated analysis of both in vivo and in vitro endpoints. First, we will employ in viva canine models of unstable angina and persistent thrombosis to evaluate the effects of brief antecedent ischemia and selective; pharmacologic A2 receptor stimulation on: coronary patency; platelet adhesion molecule expression (by flow cytometry; platelet aggregometry); and Factor XlIl-catalyzed fibrin polymerization (by quantitative light microscopy) in the evolving coronary thrombus. Second, in concurrent studies, we will assess the effects of exogenous A2 receptor stimulation on in vitro, surrogate indices of vessel patency (in vitro platelet aggregation; in vitro thrombosis/thrombolysis). Finally, to address our third hypothesis -- that the favorable effects of A2-mediated signaling observed in our experimental models have potential clinical relevance -- we will conduct an identical in vitro analysis of platelet aggregation and thrombosis/thrombolysis on blood samples obtained from human volunteers. These hypotheses, if confirmed, may ultimately aid in the design of novel therapeutic strategies aimed at enhancing vessel patency in clinical instances of unstable angina and reperfusion for the treatment of acute myocardial infarction.

描述（由申请人提供）：我们实验室的证据表明 先前的“预处理”缺血的短暂发作，除了 限制梗塞面积：（1）改善犬模型中的冠状动脉通畅性 模拟不稳定心绞痛的初次止血； (2) 提高速度 溶栓在犬凝血和持续性模型中的疗效 血栓闭塞。我们的结果进一步暗示了腺苷的释放 来自缺血/再灌注心肌，以及随后的血小板刺激 腺苷A2受体在这一现象中发挥着关键作用。然而， 负责这些改进的特定“远端”分子机制 冠状动脉通畅性尚不清楚。 血小板粘附、激活——并最终通过结合聚集 相邻血小板上纤维蛋白原与糖蛋白 (GP) IIb/IIIL 受体的关系 -- 代表了反复缺血的潜在“病理生理学” 不稳定心绞痛的情况。因此，我们的第一个假设是改进后的 冠状动脉通畅，伴有短暂的先期缺血/血小板 A2 受体 刺激是通过下调粘附表达来实现的 参与形成和稳定化的分子和/或配体 血小板聚集体——具体为 GP IIb/IIIa、P-选择素、血管性血友病 因子、PECAM 和/或 GP Ib。从不稳定的血小板“塞子”到 持久的、含有纤维蛋白的凝块涉及凝血酶催化的转化 纤维蛋白原（血小板聚集体中的分子“桥梁”）转化为纤维蛋白， 凝血酶介导的因子 XIII 和后续因子的激活 XIII-催化纤维蛋白交联。因此，我们的第二个假设是 短暂的先期缺血/A2 受体刺激引起——结果 血小板活化/聚集和粘附分子表达的变化 -- 凝血过程的改变以及凝血过程中纤维蛋白聚合的改变 促进溶解剂渗透和结合的发展，从而 加速溶栓。 这些概念将通过体内和体内的综合分析进行测试 体外终点。首先，我们将采用viva犬不稳定心绞痛模型 和持续性血栓形成来评估先前短暂缺血的影响 并且有选择性；药理 A2 受体刺激：冠状动脉通畅； 血小板粘附分子表达（通过流式细胞术；血小板 聚合度）；和因子 XIII 催化的纤维蛋白聚合（通过定量 光学显微镜）观察不断演变的冠状动脉血栓。二、同时进行 研究中，我们将评估外源性 A2 受体刺激对 体外，血管通畅性的替代指数（体外血小板聚集；在 体外血栓形成/溶栓）。最后，解决我们的第三个假设—— 在我们的研究中观察到 A2 介导的信号传导的有利影响 实验模型具有潜在的临床意义——我们将进行 血小板聚集和血栓形成/溶栓的相同体外分析 从人类志愿者获得的血液样本。这些假设，如果 证实，可能最终有助于设计新的治疗策略 旨在增强不稳定心绞痛临床病例中的血管通畅性 再灌注用于治疗急性心肌梗塞。