DOXORUBICIN CARDIOMYOPATHY IS ASSOCIATED WITH A DECREASE IN CALCIUM RELEASE CHANNEL OF THE SARCOPLASMIC-RETICULUM IN A CHRONIC RABBIT MODEL
DOXORUBICIN CARDIOMYOPATHY IS ASSOCIATED WITH A DECREASE IN CALCIUM RELEASE CHANNEL OF THE SARCOPLASMIC-RETICULUM IN A CHRONIC RABBIT MODEL
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DOI：
10.1172/jci116379
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发表时间：
1993-04-01
影响因子：
15.9
通讯作者：
BOUCEK, RJ
中科院分区：
文献类型：
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作者：
DODD, DA;ATKINSON, JB;BOUCEK, RJ
多柔比星是一种高效的癌症化疗剂，其产生的剂量依赖性心肌病限制了其临床用途。多柔比星诱导的心肌病早期阶段的形态学变化的临床和动物研究表明，肌浆网，在成年哺乳动物心脏负责肌浆钙调节的细胞内膜系统，可能是多柔比星的早期目标。为了检测慢性阿霉素治疗期间肌浆网的钙泵蛋白或钙释放通道（兰尼碱受体）的变化，家兔每周两次静脉注射阿霉素（1 mg/kg），共12至18次。配对喂养的对照组静脉注射生理盐水。通过左心室乳头肌的光镜和电镜检查对心肌病的严重程度进行评分。在离体心房肌条中测量了产生的张力。在心脏的亚细胞组分中，与对照组（0.66+/-0.02 pmol/mg; P < 0.0001）相比，多柔比星治疗组（0.33+/-0.03 pmol/mg）的[H-3]ryanodine结合减少。[H-3]ryanodine结合减少的幅度与病理评分（光镜和电镜）分级的心肌病严重程度和孤立心房肌条中发达张力的减少相关。[H-3]ryanodine结合的B（max）和免疫反应性ryanodine受体的量（通过使用序列特异性抗体的Western印迹分析）均降低，这与多柔比星处理的家兔中肌浆网钙释放通道的量降低一致。相比之下，阿霉素治疗的家兔肌浆网钙泵蛋白的量或活性没有降低。多柔比星处理不降低[H-3]ryanodine结合或骨骼肌肌浆网免疫反应性钙释放通道的数量。由于肌浆网通过循环摄取和释放大量的内部钙池来调节肌肉收缩，钙释放通道功能的改变可能导致在阿霉素心肌病中观察到的收缩和舒张异常。
Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity of cardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, [H-3]ryanodine binding was decreased in doxorubicin-treated rabbits (0.33+/-0.03 pmol/mg) compared with control rabbits (0.66+/-0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [H-3]ryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. B(max) for [H-3]ryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [H-3]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities of contraction and relaxation observed in the doxorubicin cardiomyopathy.