CARDIOPROTECTIVE EFFECT--NEW CHELATORS FOR THALASSEMIA

心肌铁毒性是地中海贫血铁超载的最严重的生命限制并发症，其发病机制的研究因未能建立模拟输血性铁沉着症的动物模型而受到严重阻碍。因此，我们已经开发了一个系统的培养大鼠心肌细胞中，铁负载与非转铁蛋白铁的结果在结构和功能异常类似含铁血黄素心肌病。在本提案中，我们希望检验以下假设：（a）可螯合的细胞不稳定铁池的消耗可能允许心脏细胞功能的恢复，通过逆转铁诱导的收缩性和节律性异常、脂质过氧化作用增加、肌膜巯基蛋白损失、溶酶体脆性增加和线粒体呼吸功能异常（B）六齿螯合剂提供可预测的保护作用，而三齿和二齿螯合剂（如L1）可能导致内部铁再分布和有害的芬顿反应的矛盾增强;（c）亲脂性螯合剂在穿透心脏细胞方面更有效，允许逆转现有损伤，而亲水性螯合剂可具有上级能力来防止铁诱导的损伤。使用肝细胞和网状内皮铁储备的选择性放射性铁探针的高输血大鼠将用于确定可用于体内动员的铁池。将在两个实验系统中探索抗坏血酸盐增强螯合效率和α-生育酚防止过氧化损伤的能力。拟议的研究代表了新铁螯合剂的药理化学和潜在临床应用之间的重要联系，通过深入了解其作用机制和心脏保护作用，为地中海贫血患者铁过载管理的新策略的开发提供了重要的非正式信息。

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.