MYOCARDIAL PROTECTION WITH A1 RECEPTOR OVEREXPRESSION

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DESCRIPTION (adapted from the applicant's abstract): Myocardial damage from ischemia with coronary vascular disease causes significant morbidity and mortality. The investigators have been studying the effects of endogenous protective mechanisms, such as adenosine, to provide tolerance to ischemia. The investigators note that acting at A1 receptors, adenosine reduces ischemia-reperfusion injury and mediates ischemic preconditioning. In addition they state that the heart must also adapt to changing metabolic needs to avoid injury from imbalances in myocardial oxygen supply and demand. When the metabolic demands of the heart are greater than the oxygen supply (demand ischemia), the investigators indicate that adenosine acts via the A1 adenosine receptor to directly protect the myocardium. Thus, the investigators conclude that activation of A1 receptors can provide protection to the heart during bot ischemia and "demand ischemia". This proposal adopts the approach of overexpressing myocardial A1 adenosine receptors with transgenic techniques to enhance the intrinsic tolerance of the myocardium to ischemia reperfusion, and demand ischemia. The central hypothesis of this proposal is that a transgenic model of increased cardiac A1 receptors will have increased protection from ischemia- reperfusion and from decreases in the oxygen supply to demand ratio ("demand ischemia"). The long range goal is an integrated analysis of the role of A1 receptors in cardioprotection in order to identify the mechanism of this protection. The investigators will evaluate the functional, bioenergetic, biochemical, and ultrastructural response to ischemia in transgenic mice and will assess the mechanism(s) of A1 adenosine receptor-mediated myocardial protection by identifying the signaling pathways involved and evaluating the cellular mechanisms by assessing calcium transport and glucose metabolism.