MEMBRANE PEROXIDATION IN ADRIAMYCIN HEART DISEASE

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Rats treated chronically with adriamycin will be studied as an animal model for the development of adriamycin-induced heart muscle disease. The hypothesis which will be tested is that cardiomyopathy may arise as a consequence of adriamycin-initiated free radical reactions leading to the peroxidation of lipids and that this process causes disruption of cardiac membranes, either directly through structural alterations or indirectly through metabolic perturbations, resulting ultimately in cardiac muscle disease. The further hypothesis that lipid peroxides associated with serum lipoproteins, found in the serum of rats treated chronically with adriamycin, may act as secondary toxins mediating the development of cardiomyopathy will be investigated. Biochemical methods will be used to determine the effects of these serum lipid peroxides and model peroxides on cell viability, intracellular oxidation-reduction state and extracellular release of glutathione, and calcium homeostasis. Isolated cardiac myocytes and the perfused heart will be utilized as experimental systems for the studies. In addition, isolated hepatocytes and the perfused liver will also be employed in order to evaluate the organ selectivity of biochemical perturbations. The possible hepatic origin of the serum lipid peroxides in rats treated chronically with adriamycin will be investigated by biochemical fractionation techniques. Chromatographic and spectroscopic methods will be employed to characterize the chemical structures of the serum lipid peroxides. In addition, the relative roles of cardiac and hepatic adriamycin reduction-autooxidation in toxicity will be studied at the levels of isolated cells (cardiac myocytes and hepatocytes) and perfused organs (heart and liver). Experiments will test the effects of adriamycin in vitro on glutathione metabolism, generation of activated species of oxygen, lipid peroxidation, calcium homeostasis, and cell viability. The significance of diminished cardiac lipoprotein lipase activity, observed in rats treated chronically with adriamycin, will be evaluated by measurements of serum lipoprotein and lipid utilization in perfused heart preparations. The effect of the serum lipoprotein-peroxides on cardiac lipoprotein lipase will also be tested. Additional studies will characterize the effects of chronic adriamycin administration on cardiac subcellular membranes. These will include localization of iminopropene products of lipid peroxidation, free radical generation activity, bioenergetic functions, and calcium uptake and release by sarcoplasmic reticulum. These studies may contribute toward an understanding of the pathogenesis of adriamycin-induced heart muscle disease.