Calpain and Calpastatin Regulation of Reperfusion Injury

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DESCRIPTION (provided by applicant): Congenital heart disease is the number 1 cause of death from birth defects in the first year of life. Although corrective or palliative surgery for most congenital heart defects can be undertaken in infancy, repair is still associated with mortality and morbidity exceeding that of most pediatric surgical procedures. Cardiopulmonary bypass and myocardial ischemia is typically required for repair and can result in myocardial dysfunction that is temporary, such as myocardial stunning, or permanent, such as occurs with apoptosis. Myocardial protective strategies for infants and children are limited and often are only extrapolations of adult therapies. Reperfusion of ischemic heart stimulates the activity of cysteine proteases called calpains and their endogenous inhibitor, calpastatin. Calpain activity is associated with interruption of calcium-regulated contraction, degradation of contractile proteins, and enhanced cell death. The long-term goal of this proposal is to define mechanisms of myocardial dysfunction after ischemia and reperfusion in children. The immediate goal is to identify pathways that facilitate development of interventions to reduce postoperative reperfusion injury. The hypothesis is that calpain and calpastatin pathways are critical mediators of reperfusion injury in immature myocardium. The specific aims of this project are: 1) determine the role of nuclear factor-kappaB regulation by calpain and calpastatin in myocardial dysfunction associated with reperfusion in an immature animal model, 2) define the role of calpain in mediating cardiac apoptosis associated with reperfusion of ischemic myocardium, and 3) determine regulatory mechanisms of calpastatin activity after reperfusion. A piglet model of cardiopulmonary bypass and circulatory arrest and in vitro culture of neonatal cardiomyocytes examine the roles of calpain and calpastatin in reperfusion injury of the immature cardiopulmonary system. Determining calpain and calpastatin regulation of these pathways identifies therapeutic targets to reduce postoperative myocardial dysfunction in pediatric patients.