Adenosine Receptor-Mediated Protection in Reperfused MI

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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.