MEMBRANE PEROXIDATION IN ADRIAMYCIN HEART DISEASE

长期使用阿霉素治疗的大鼠将作为动物模型进行研究 用于阿霉素诱导的心肌疾病的发展。这个 将被检验的假说是心肌病可能作为一种 阿霉素引发的自由基反应导致的后果 脂质过氧化和这一过程导致心脏功能紊乱 膜，直接通过结构改变或间接 通过代谢紊乱，最终导致心肌 疾病。脂质过氧化与血清相关的进一步假说 脂蛋白，发现在长期用药的大鼠的血清中 阿霉素可能作为次生毒素参与肿瘤的发生发展。 将对心肌病进行调查。将使用生化方法来 测定这些血清过氧化脂质和模型过氧化产物对小鼠的影响 细胞活力、细胞内氧化还原状态和细胞外 释放谷胱甘肽和钙稳态。分离的心肌细胞 而灌流的心脏将被用作实验系统 学习。此外，分离的肝细胞和灌流的肝脏将 也可以用来评价生物化学的器官选择性 微扰。慢性肝炎患者血清过氧化脂质可能来源于肝脏 长期使用阿霉素治疗的大鼠将通过 生化分级技术。色谱学和光谱学 将使用各种方法来表征该化合物的化学结构 血清过氧化脂质。此外，心脏和心脏的相对作用 毒性中的肝脏阿霉素还原-自氧化研究将在 分离的细胞(心肌细胞和肝细胞)和 灌流器官(心脏和肝脏)。实验将测试的效果 阿霉素体外对谷胱甘肽代谢的影响 氧的种类、脂质过氧化、钙稳态和细胞 生存能力。心肌脂蛋白脂酶活性降低的意义 在长期使用阿霉素治疗的大鼠中观察到的活动将是 通过测定血清脂蛋白和脂类利用率来评价 灌流的心脏制剂。过氧化脂质对血清脂蛋白的影响 对心肌脂蛋白脂酶也将进行检测。更多的研究将 慢性阿霉素给药对心脏的影响 亚细胞膜。这些将包括亚氨基丙烯的本地化。 脂质过氧化产物，自由基生成活性， 生物能量功能与肌浆钙的吸收和释放 网状结构。这些研究可能有助于理解 阿霉素性心肌病的发病机制。

Rats treated chronically with adriamycin will be studied as an animal model for the development of adriamycin-induced heart muscle disease. The hypothesis which will be tested is that cardiomyopathy may arise as a consequence of adriamycin-initiated free radical reactions leading to the peroxidation of lipids and that this process causes disruption of cardiac membranes, either directly through structural alterations or indirectly through metabolic perturbations, resulting ultimately in cardiac muscle disease. The further hypothesis that lipid peroxides associated with serum lipoproteins, found in the serum of rats treated chronically with adriamycin, may act as secondary toxins mediating the development of cardiomyopathy will be investigated. Biochemical methods will be used to determine the effects of these serum lipid peroxides and model peroxides on cell viability, intracellular oxidation-reduction state and extracellular release of glutathione, and calcium homeostasis. Isolated cardiac myocytes and the perfused heart will be utilized as experimental systems for the studies. In addition, isolated hepatocytes and the perfused liver will also be employed in order to evaluate the organ selectivity of biochemical perturbations. The possible hepatic origin of the serum lipid peroxides in rats treated chronically with adriamycin will be investigated by biochemical fractionation techniques. Chromatographic and spectroscopic methods will be employed to characterize the chemical structures of the serum lipid peroxides. In addition, the relative roles of cardiac and hepatic adriamycin reduction-autooxidation in toxicity will be studied at the levels of isolated cells (cardiac myocytes and hepatocytes) and perfused organs (heart and liver). Experiments will test the effects of adriamycin in vitro on glutathione metabolism, generation of activated species of oxygen, lipid peroxidation, calcium homeostasis, and cell viability. The significance of diminished cardiac lipoprotein lipase activity, observed in rats treated chronically with adriamycin, will be evaluated by measurements of serum lipoprotein and lipid utilization in perfused heart preparations. The effect of the serum lipoprotein-peroxides on cardiac lipoprotein lipase will also be tested. Additional studies will characterize the effects of chronic adriamycin administration on cardiac subcellular membranes. These will include localization of iminopropene products of lipid peroxidation, free radical generation activity, bioenergetic functions, and calcium uptake and release by sarcoplasmic reticulum. These studies may contribute toward an understanding of the pathogenesis of adriamycin-induced heart muscle disease.