Research on the pathogenesis of myocardial iron toxicity, the most critical life-limiting complication of thalassemic iron overload, has been seriously hindered by failure to develop an animal model simulating transfusional siderosis. Consequently, we have developed a system of cultured rat cardiomyocytes in which iron-loading with non-transferrin iron results in structural and functional abnormalities analogous with hemosiderotic myocardiopathy. In the present proposal we wish to test the hypothesis that (a) depletion of the chelatable cellular labile iron pool may permit recovery of heart cell function, documented by reversal of the iron-induced abnormalities in contractility and rhythmicity, increased lipid peroxidation, loss of sarcolemmal thiolic proteins, increased lysosomal fragility and abnormal mitochondrial respiratory function (b) that hexadentate chelators offer a predictable protective effect whereas tridentate and bidentate chelators (such as L1) may cause internal iron redistribution and a paradoxical enhancement of the harmful Fenton reaction and; (c) that lipophilic chelators are more efficient in penetrating heart cells allowing reversal of existing damage whereas hydrophilic chelators may have superior ability to prevent iron-induced damage. Hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores will be used to define the pools of iron available for in vivo mobilization. The ability of ascorbate to enhance chelating efficiency and of alpha-tocopherol to prevent peroxidative damage will be explored in both experimental systems. The proposed studies represent an essential link between the pharmacologic chemistry and potential clinical application of new iron chelators by allowing insight into their mechanism of action and cardioprotective effect, providing vital informal for the development of new strategies for the management of iron overload in thalassemic patients.
| Link, Gabriela; Ponka, Prem; Konijn, Abraham M et al. (2003) Effects of combined chelation treatment with pyridoxal isonicotinoyl hydrazone analogs and deferoxamine in hypertransfused rats and in iron-loaded rat heart cells. Blood 101:4172-9 |
| Hershko, C; Konijn, A M; Nick, H P et al. (2001) ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture. Blood 97:1115-22 |
| Link, G; Konijn, A M; Breuer, W et al. (2001) Exploring the ""iron shuttle"" hypothesis in chelation therapy: effects of combined deferoxamine and deferiprone treatment in hypertransfused rats with labeled iron stores and in iron-loaded rat heart cells in culture. J Lab Clin Med 138:130-8 |
