Adenosine Receptor-Mediated Protection in Reperfused MI

描述（由申请人提供）：A2A腺苷受体（A2AAR）激动剂是已知的血管扩张剂，其也在低剂量下抑制炎症。 A2 AAR激活可通过抑制白细胞活化、内皮细胞粘附和中性粒细胞聚集来减轻心肌梗死（MI）再灌注损伤。 虽然A2AAR激活的心肌梗死保护作用已被充分证明，但其对左心室（LV）重塑慢性过程的长期影响尚未进行任何详细研究。 这个问题是至关重要的，特别是考虑到以前的抗炎药试验的混合结果。 我们假设，在再灌注期间短暂给予高选择性A2AAR激动剂不仅可以减轻再灌注损伤并减少MI动物模型中的梗死面积，而且这种治疗还可以通过抑制全身炎症激活和随后的LV重塑来长期保护LV功能。 我们提出了一系列完整的动物实验，采用一组互补的尖端，非侵入性成像模式：i）表征在大的，前壁MI的再灌注过程中A2AAR激活的抗炎作用和ii）确定这种治疗对梗死面积减少和随后的梗死愈合和LV重塑的影响。 在初步研究中，我们已经表明，A2AAR的高选择性激动剂在MI的小型和大型动物模型中均减少了梗死面积（即，老鼠和狗）。 此外，我们已经在心脏成像（核，超声心动图和心脏MRI）中实施了先进的技术，以非侵入性地评估动物模型中的梗死面积，LV功能，心肌灌注和炎症。 在这项研究中，将使用特定的药物、基因操作的小鼠和强大的非侵入性成像技术来评估梗死保留治疗的长期结果。 将采用跨心脏病学、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的多学科方法。 具体目标是：1）使用A2AAR“敲除”小鼠和骨髓移植实验，在MI的鼠模型中表征短期A2AAR激活的心脏保护作用的潜在机制及其对LV重构的影响。 2)在再灌注犬中，使用常规超声造影和放射性核素成像技术，确定短期A2AAR激活与腺苷相比的最佳抗炎和保护梗死效果。 3)在血栓性冠状动脉闭塞和再流的慢性犬模型中，使用常规免疫组织化学技术结合对比增强心脏MRI，表征短期A2 AAR激活对梗死面积缩小、LV功能、LV重塑和梗死愈合的长期结局的影响。

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.