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，在低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活化、内皮粘附和中性粒细胞积累来减轻心肌梗死（MI）时的再灌注损伤。虽然A2AAR激活的梗死保护作用已被充分证实，但其对左室（LV）重塑慢性过程的长期影响尚未得到详细研究。这个问题是至关重要的，特别是考虑到以往抗炎药试验的混合结果。我们假设，在心肌梗死动物模型中，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和减少梗死面积，而且这种治疗还可以通过抑制全身炎症激活和随后的左室重塑来长期保护左室功能。我们提出了一系列的全动物实验，采用一套互补的尖端、非侵入性成像方式来：1)表征A2AAR在大的前侧心肌梗死再灌注期间激活的抗炎作用；2)确定这种治疗对梗死面积缩小、随后的梗死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心肌梗死动物模型（即小鼠和狗）的梗死面积。此外，我们采用了先进的心脏成像技术（核、超声心动图和心脏MRI），在动物模型中无创评估梗死面积、左室功能、心肌灌注和炎症。在这项资助中，将使用特定的药理学药物、基因操纵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。将采用多学科方法，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等领域。具体目的是：1)通过A2AAR“敲除”小鼠和骨髓移植实验，表征短期A2AAR激活对心肌梗死小鼠模型心脏保护作用的机制及其对左室重构的影响。2)利用常规超声心动图和放射性核素成像技术，确定再灌注犬短期A2AAR激活与腺苷相比的最佳抗炎和梗死保护效果。3)在血栓性冠状动脉闭塞和再流的慢性狗模型中，利用常规免疫组织化学技术结合心脏MRI增强对比，表征短期A2AAR激活对梗死面积缩小、左室功能、左室重塑和梗死愈合的长期结果的影响。

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.