CARDIOPROTECTIVE EFFECT--NEW CHELATORS FOR THALASSEMIA

心肌铁中毒是地中海贫血铁负荷过高的最关键的生命限制性并发症，由于未能建立模拟输血铁质沉着症的动物模型，其发病机制的研究受到严重阻碍。因此，我们开发了一种培养大鼠心肌细胞的系统，在该系统中，铁负载非转铁蛋白铁导致类似含铁血黄素心肌病的结构和功能异常。在目前的方案中，我们希望检验这样的假设：(A)可螯合的细胞不稳定铁库的耗尽可能允许心脏细胞功能的恢复，证明通过逆转铁诱导的收缩和节律性异常、脂质过氧化增加、肌膜硫代蛋白丢失、溶酶体脆性增加和线粒体呼吸功能异常来记录的；(B)六齿螯合剂提供可预测的保护作用，而三齿和双齿螯合剂(如L1)可能导致内部铁重新分配和有害Fenton反应的矛盾增强；(C)亲脂性螯合剂在穿透心肌细胞方面更有效，从而可以逆转现有的损伤，而亲水性螯合剂可能具有更好的防止铁诱导的损伤的能力。超输注的大鼠带有选择性的肝细胞和网状内皮细胞铁库的放射性铁探针，将用于确定可用于活体动员的铁库。抗坏血酸提高螯合效率的能力和α-生育酚防止过氧化损伤的能力将在这两个实验系统中进行探索。拟议的研究代表了新铁络合剂的药理化学和潜在的临床应用之间的重要联系，使人们能够深入了解它们的作用机制和心脏保护作用，为开发治疗地中海贫血患者铁超载的新策略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.