Adriamycin continues to be one of the most widely prescribed antineoplastic agents despite the high incidence of life-threatening cardiomyopathy. Because of the abundance of mitochondria and the strict dependence of the myocardium on oxidative phosphorylation, the applicant has focused on the inhibition of mitochondrial bioenergetics as being critical to the cardioselective toxicity of the drug. The applicant has demonstrated that adriamycin interferes with mitochondrial calcium regulation to initiate a futile, energy-consuming cycling of calcium across the inner mitochondrial membrane. The result is that cardiac mitochondria from adriamycin-treated rats express a dose-dependent increase in sensitivity to calcium-induced membrane depolarization and inhibition of oxidative phosphorylation. This is also manifested in cardiac myocytes isolated from adriamycin-treated rats as an increased vulnerability to calcium-induced cell killing in vitro. Of particular significance is that the effects on both mitochondrial bioenergetics and myocytes injury are prevented by inhibitors of mitochondrial calcium cycling. The goal of the proposed investigation is to extend these recent observations to determine whether, as a consequence of interfering with mitochondrial calcium regulation, adriamycin disturbs the normal cell signaling function of mitochondria wherein the rate of oxidative phosphorylation is adjusted to meet changes in metabolic demand. To this end, the investigators will evaluate various bioenergetics and functional characteristics of perfused hearts, cardiac myocytes and cardiac mitochondria isolated from adriamycin- and saline-treated rats. The effects of agents or metabolic interventions known to elicit transient increases in cytosolic calcium on mitochondria bioenergetics and contractile performance of these preparations will be compared in the absence and presence of inhibitors of mitochondrial calcium cycling. Since many of these agents, such as cardiac glycosides and beta-adrenergic agonists, are frequently prescribed to combat the cardiac failure associated with adriamycin therapy, the results may reveal important adverse drug interactions encountered clinically. The preliminary evidence suggests a high probability that the investigation will yield new understanding and strategies for limiting the cardiomyopathy associated with this important cancer chemotherapeutic agent. Further, much of the knowledge regarding mitochondrial myopathies will be readily transposed to improve our understanding of mechanisms of tissue injury caused by assorted other xenobiotics that, like adriamycin, are known to interfere with mitochondrial calcium regulation and bioenergetics.
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