Adenosine Receptor-Mediated Protection in Reperfused MI

再灌注心肌梗死中腺苷受体介导的保护

• 批准号: 6914991
• 负责人: George Allan Beller
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914991
• 关键词: antiinflammatory agents; bioimaging /biomedical imaging; cardiovascular imaging /visualization; cytoprotection; disease /disorder model; dogs; echocardiography; immunocytochemistry; laboratory mouse; magnetic resonance imaging; myocardial infarction; purinergic receptor; radionuclide imaging /scanning; reperfusion; stimulant /agonist

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，也可在相当低的剂量下抑制炎症。已知A2AAR活化可通过抑制白细胞活化、内皮细胞黏附和中性粒细胞聚集来减轻心肌梗死再灌注损伤。虽然A2AAR激活对心肌梗死的保护作用已有很好的文献记载，但其对慢性左心室(LV)重塑过程的长期影响尚未得到详细研究。这个问题至关重要，特别是考虑到以前的抗炎药试验结果喜忧参半。我们推测，在再灌注期间短暂应用高选择性的A2AAR激动剂不仅有助于减轻再灌注损伤和缩小心肌梗死动物模型的梗塞范围，而且这种治疗还将通过抑制全身炎症激活和随后的左室重构来长期保存左室功能。我们提出了一系列完整的动物实验，使用一套互补的尖端非侵入性成像方法来：i)在大面积、前壁MI的情况下，表征再灌注期间A2AAR激活的抗炎作用；ii)确定这种治疗对梗塞面积缩小和随后的梗塞愈合和左室重构的影响。在初步研究中，我们已经表明，一种高选择性的A2AAR激动剂在小鼠和大鼠(即小鼠和狗)的心肌梗塞动物模型中都能减少梗塞范围。此外，我们实施了先进的心脏成像技术(核成像、超声心动图和心脏MRI)，以非侵入性地评估动物模型的心肌梗死范围、左心功能、心肌灌注和炎症。在这笔赠款中，将使用特定的药理学药物、基因操纵的小鼠和强大的非侵入性成像技术来评估脑梗塞保留治疗的长期结果。将使用一种多学科的方法，跨越心脏病学、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等领域。其具体目的是：1)利用A2AAR“敲除”小鼠和骨髓移植实验，表征A2AAR短期激活对心肌梗死小鼠模型的心脏保护作用及其对左室重构的影响的机制。2)使用声学造影和放射性核素成像的常规技术，确定短期A2AAR激活与腺苷相比的最佳抗炎和脑梗塞保护效果。3)应用常规免疫组织化学技术结合心脏MRI增强扫描技术，研究A2AAR短期激活对慢性犬血栓闭塞再流模型心肌梗死面积缩小、左室功能、左室重构和心肌梗死愈合的影响。