CARDIAC MYOCYTES CULTURED BEATING--IRON OVERLOAD MODEL

心肌毒性是最重要的危及生命的并发症

Myocardial toxicity is the most important life-limiting complication of iron overload. Research on myocardial iron toxicity has been seriously hindered by the lack of a satisfactory experimental model. We have previously shown that iron-loading of cultured rat heart cells results in abnormal contractility and electrophysiologic behaviour and increased peroxidation of membrane lipids, reversible by deferoxamine treatment. In the next phase of our studies we intend to clarify the relation between structural alterations in membrane lipid architecture and the functional abnormalities induced by iron toxicity. These studies will proceed along 3 lines: I. Structural changes in lipid membranes isolated from the sarcolemma, mitochondria and lysosomes will be characterized by measuring their phospholipid, lysophospholipid, phosphatidyl ethanolamine/phosphatidyl choline content, and by identifying membrane lipid moieties in direct contact with the external environment and accessible for radioiodinationor interaction with the with trinitrobenzene sulphonate. II. Abnormal organelle function will be documented in (a) the sarcolemma by measuring transmembrane potential and calcium uptake; (b) in mitochondria by measuring ADP-stimulated and ADP- limited respiration and respiratory control ratio, and; (c) in lysosomes by measuring their fragility documented by latent and sedimentable acid hydrolase activities. III. The ability of ascorbate, alpha-tocopherol, hypoxia and deferozamine to modify or prevent the iron-induced abnormalities will be explored. Abnormalities in organelle function will be correlated with alterations in membrane architecture. The primary target of iron toxicity will be identified by the timing and extent of structural or functional abnormalities observed in the various organelles obtained from iron loaded heart cells. Information gained in these studies will help in clarifying the pathogenesis of mypocardial disease in iron overload, the manner in which hypoxia, iron chelating agents and antioxidants may modify or prevent iron-induced damage to the heart, and may be useful in developing more rational and effective methods for the management of transfusional iron overload.