A3 Adenosine Receptors Cardioprotective Mechanisms

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DESCRIPTION (provided by applicant): The goal of this research is to define the mechanisms by which A3 adenosine receptors (ARs) protect against myocardial ischemia/reperfusion injury. We will test the hypothesis that A3ARs are protective by multiple mechanisms including preservation of mitochondrial function, reduction of apoptosis, and attenuation of inflammation. We predict that the A3AR signals via kinase signaling pathways that ultimately results in protection by activation of mitochondrial KATP channels. A key feature of our hypothesis is that we predict that A3ARs are expressed in cardiac myocytes. We will test these hypotheses by examining the effect of selective A3AR agonists in an isolated mouse heart model of global ischemia/reperfusion and a clinically relevant in vivo dog model of infarction. The isolated mouse heart model will be used to correlate post-ischemic contractile function (left ventricular pressure) and cell necrosis (LDH released) with metabolic state (high-energy phosphates), mitochondrial integrity (mitochondrial membrane potential, respiration, and rate of ATP synthesis), apoptosis (DNA fragmentation, TUNEL staining, caspase activation), and pro-inflammatory cytokine signaling (NF kappa B activation, TNF alpha production). The in vivo dog model of infarction will be used to compare infarct size with markers of inflammation (neutrophil infiltration). The mitochondrial specific KATP channel blocker sodium 5-hydroxydecanoate will be used to delineate the role of mitochondrial KATP channels in preserving mitochondrial and cardiac function. Experiments will be performed to determine whether A3ARs signal via specific protein kinases (PKC-epsilon or delta; PI-3/akt kinase) and/or generation of reactive oxygen species. Information obtained from these studies will advance the understanding of the fundamental questions involved in cellular protection. The results of theses studies should also provide new insights into the therapeutic utility of targeting A3ARs in patients with ischemic heart disease.