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Adenosine Receptor-Mediated Protection in Reperfused MI

再灌注心肌梗死中腺苷受体介导的保护

基本信息

批准号：
7456563
负责人：
George Allan Beller
金额：
$ 36.15万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7456563
关键词：
Acute Acute myocardial infarction Address Adenosine Adenosine A2A Receptor Adherence Adhesions Agonist Animal Experiments Animal Model Animals Anterior Anti-Inflammatory Agents Anti-inflammatory Appendix Area Attenuated Blood Platelets Blood Vessels Blood flow Bone Marrow Bone Marrow Transplantation Canis familiaris Cardiac Cardiac Myocytes Cardiology Cell Lineage Cells Cellular biology Chronic Cicatrix Clinical Trials Contrast echocardiography procedure Coronary Coronary Occlusions Coupled Dexamethasone Dose Echocardiography End Point Endothelial Cells Equilibrium Functional disorder Genetic Grant Healed Image Imaging Techniques Immune system Immunohistochemistry Immunologics Immunology In Situ Hybridization Incidence Infarction Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Intervention Invaded Invasive Knockout Mice Laboratories Left Left Ventricular Dysfunction Left Ventricular Function Left Ventricular Remodeling Leukocytes Light Magnetic Resonance Imaging Marrow Measures Mediating Methods Microbubbles Microspheres Modality Modeling Molecular Molecular Biology Molecular Genetics Mono-S Mus Myocardial Myocardial Infarction Myocardial perfusion Myocardial rupture Myocardium Neutrophil Activation Neutrophil Infiltration Nuclear Outcome Pathology Patients Perfusion Personal Satisfaction Pharmacology Physiological reperfusion Physiology Prevention Process Purinergic P1 Receptors Qualifying Radioactive Radiology Specialty Radionuclide Imaging Receptor Activation Reperfusion Injury Reperfusion Therapy Research Respiratory Burst Role Series Specificity Steroids Structure Study Section T-Lymphocyte Techniques Therapeutic Therapeutic Intervention Time Tissues Translating Transplantation Vasodilator Agents Ventricular Wound Healing adenosine receptor activation clinically relevant cytokine eosinophil expectation experience functional status genetic manipulation healing heart dimension/size improved insight interdisciplinary approach leukocyte activation macrophage mast cell mouse model myocardial infarct sizing neutrophil novel receptor repaired research study response restoration size thrombolysis

项目摘要

DESCRIPTION (provided by applicant): Agonists of the A2A adenosine receptor (A2AAR) are known vasodilators that also inhibit inflammation at substantially lower doses. It is has long been known that A2AAR activation can attenuate reperfusion injury during myocardial infarction (MI) by inhibiting leukocyte activation, endothelial adhesion and neutrophil accumulation. While the infarct sparing effect of A2AAR activation is well documented, its long-term impact on the chronic process of left ventricular (LV) remodeling has yet to be studied in any detail. This question is critical, particularly in light of the mixed outcomes from previous trials of anti-inflammatory agents. We hypothesize that brief administration of a highly-selective A2AAR agonist during reperfusion will serve not only to attenuate reperfusion injury and reduce infarct size in animal models of MI, but that this treatment will also preserve LV function in the long-term by dampening systemic inflammatory activation and subsequent LV remodeling. We propose a series of whole animal experiments employing a complementary set of cutting-edge, non-invasive imaging modalities to: i) characterize the anti-inflammatory role of A2AAR activation during reperfusion in the setting of large, anterior MI and ii) determine the impact of such treatment on infarct size reduction and subsequent infarct healing and LV remodeling. In preliminary studies, we have shown that a highly-selective agonist of the A2AAR reduces infarct size in both small and large animal models of MI (i.e., mouse and dog). Furthermore, we have implemented advanced techniques in cardiac imaging (nuclear, echocardiography, and cardiac MRI) to non-invasively assess infarct size, LV function, myocardial perfusion, and inflammation in animal models. In this grant, the long-term outcome of infarct-sparing therapy will be assessed using specific pharmacologic agents, genetically-manipulated mice and powerful non-invasive imaging techniques. A multidisciplinary approach will be used that spans the fields of cardiology, immunology, radiology, cardiac physiology, pathology, cell biology and molecular genetics. The specific aims are to: 1) Characterize the mechanisms underlying the cardioprotective effect of short-term A2AAR activation and its impact on LV remodeling in a murine model of MI using A2AAR "knock-out" mice and bone-marrow transplantation experiments. 2) Determine the optimal anti-inflammatory and infarct-sparing effects of short-term A2AAR activation compared to adenosine in reperfused dogs using conventional techniques with contrast echocardiography and radionuclide imaging. 3) Characterize the impact of short-term A2AAR activation on the long-term outcomes of infarct size reduction, LV function, LV remodeling and infarct healing in the chronic dog model of thrombotic coronary occlusion and reflow using conventional immunohistochemical techniques coupled with contrast-enhanced cardiac MRI.

描述（由申请人提供）：A2A腺苷受体（A2AAR）的激动剂是已知的血管扩张剂，其在显着较低的剂量下也能抑制炎症。人们早就知道，A2AAR 激活可以通过抑制白细胞激活、内皮粘附和中性粒细胞积累来减轻心肌梗死 (MI) 期间的再灌注损伤。虽然 A2AAR 激活的梗塞保护作用已有充分记录，但其对左心室 (LV) 重塑慢性过程的长期影响尚未得到详细研究。这个问题至关重要，特别是考虑到之前抗炎药物试验的结果好坏参半。我们假设，在再灌注期间短暂施用高度选择性的 A2AAR 激动剂不仅可以减轻 MI 动物模型的再灌注损伤并减少梗死面积，而且这种治疗还可以通过抑制全身炎症激活和随后的左心室重塑来长期保护左心室功能。我们提出了一系列整体动物实验，采用一套互补的尖端、非侵入性成像方式来：i）表征大面积前部心肌梗塞再灌注过程中 A2AAR 激活的抗炎作用，以及 ii）确定这种治疗对梗塞面积缩小以及随后的梗塞愈合和左室重塑的影响。在初步研究中，我们已经表明，A2AAR 的高选择性激动剂可以减少小型和大型 MI 动物模型（即小鼠和狗）的梗塞面积。此外，我们还采用先进的心脏成像技术（核、超声心动图和心脏 MRI）来无创评估动物模型中的梗死面积、左心室功能、心肌灌注和炎症。在这笔资助中，将使用特定的药物制剂、基因操作小鼠和强大的非侵入性成像技术来评估梗塞保留治疗的长期结果。将采用跨学科方法，涵盖心脏病学、免疫学、放射学、心脏生理学、病理学、细胞生物学和分子遗传学领域。具体目标是： 1) 使用 A2AAR“敲除”小鼠和骨髓移植实验，描述短期 A2AAR 激活的心脏保护作用的潜在机制及其对 MI 小鼠模型中左室重塑的影响。 2) 使用超声心动图和放射性核素成像等常规技术，确定再灌注狗中短期 A2AAR 激活与腺苷相比的最佳抗炎和梗塞保护效果。 3) 使用常规免疫组织化学技术结合对比增强心脏 MRI，描述短期 A2AAR 激活对血栓性冠状动脉闭塞和再流慢性狗模型中梗死面积缩小、左心室功能、左心室重塑和梗死愈合的长期结果的影响。