Understanding the mechanism of myocardial iron toxicity in hemochromatosis is seriously hindered by the lack of an appropriate experimental model. We intend to study the effects of iron loading and chelation on an in vitro system of beating rat cardiac myocytes in culture. Iron loading in these cells results in impaired contractility and automaticity, reversed by iron chelation. The objective of the proposed studies is to characterize the mechanism of iron toxicity resulting in impaired myocyte function, and the conditions whereby it may be prevented or modified. The effect of iron loading will be studied along 3 lines: I. Mechanism of iron uptake by myocardial cells: the effect of iron concentration, temperature and metabolic inhibitors; dependence of iron uptake on transferrin receptor synthesis, and; the effect of iron chelators on intracellular distribution and mobilization of iron. II. Effect of iron loading on membrane structure: maloynldialdehyde formation reflecting free-radical induced lipid peroxidation; phospholipid, lysophospholipid, phosphatidyl ethanolamine/phosphatidyl choline ratio in the isolated sarcolemma; alterations in membrane architecture reflected in the distribution of membrane lipid moieties in contact with the extracellular medium as identified by a radioiodination technique. III. Effect of iron loading on myocyte contractility, action potential and calcium uptake; site of primary injury defined by pharmacophysiologic studies employing drugs neutralizing the negative inotropic effect of iron. Variables to be tested in all 3 phases include composition of culture medium, modification of iron toxicity by coexistent hypoxia, ascorbic acid, alpha tocopherol and other antioxidants, and the ability of iron chelating drugs to prevent or reverse iron toxicity. Information gained in these studies may help in understanding the mechanism of acute iron toxicity and, less directly, of chronic iron toxicity resulting in myocardiopathy in clinical conditions associated with iron overload, and the manner in which iron chelating agents, free radical scavengers and antioxidants may prevent or modify the severity of iron induced damage. Such information may be helpful in the developmnet of a more rational approach to the management of transfusional iron overload in thalassemia and other iron loading anemias.

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National Heart, Lung, and Blood Institute (NHLBI)
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Hematology Subcommittee 2 (HEM)
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Hebrew University of Jerusalem
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Link, G; Pinson, A; Hershko, C (1993) Iron loading of cultured cardiac myocytes modifies sarcolemmal structure and increases lysosomal fragility. J Lab Clin Med 121:127-34
Hershko, C; Link, G; Tzahor, M et al. (1993) Anthracycline toxicity is potentiated by iron and inhibited by deferoxamine: studies in rat heart cells in culture. J Lab Clin Med 122:245-51
Hershko, C; Link, G; Tzahor, M et al. (1993) The role of iron and iron chelators in anthracycline cardiotoxicity. Leuk Lymphoma 11:207-14
Hershko, C (1992) Iron chelators in medicine. Mol Aspects Med 13:113-65
Shiloh, H; Iancu, T C; Bauminger, E R et al. (1992) Deferoxamine-induced iron mobilization and redistribution of myocardial iron in cultured rat heart cells: studies of the chelatable iron pool by electron microscopy and Mossbauer spectroscopy. J Lab Clin Med 119:428-36
Zevin, S; Link, G; Grady, R W et al. (1992) Origin and fate of iron mobilized by the 3-hydroxypyridin-4-one oral chelators: studies in hypertransfused rats by selective radioiron probes of reticuloendothelial and hepatocellular iron stores. Blood 79:248-53
Link, G; Athias, P; Grynberg, A et al. (1991) Iron loading modifies beta-adrenergic responsiveness in cultured ventricular myocytes. Cardioscience 2:185-8
Hershko, C; Link, G; Pinson, A et al. (1991) Iron mobilization from myocardial cells by 3-hydroxypyridin-4-one chelators: studies in rat heart cells in culture. Blood 77:2049-53
Hershko, C; Link, G; Pinson, A (1990) Principles of iron chelating therapy. Semin Hematol 27:91-4
Grady, R W; Hershko, C (1990) An evaluation of the potential of HBED as an orally effective iron-chelating drug. Semin Hematol 27:105-11

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