Sussman M A, Hamm-Alvarez S F, Vilalta P M, Welch S, Kedes L
Department of Biochemistry and Molecular Biology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Circ Res. 1997 Jan;80(1):52-61. doi: 10.1161/01.res.80.1.52.
Loss of myofilaments has been observed in both adaptive cardiac responses (i.e., hypertrophy) as well as in chemotheraputic use of antineoplastic drugs with cardiotoxic side effects (i.e., doxorubicin). An understanding of the degenerative process is a prerequisite for determining approaches to limit the cardiomyopathic changes associated with chronic heart disease or long-term chemotheraputic treatments. However, little is known about the specific events and molecular changes that initiate the degenerative process. To study this process, neonatal rat cardiomyocytes were treated with doxorubicin, which induced rapid and widespread thin-filament degeneration as observed by fluorescence confocal microscopy. Which demonstrated deterioration of sarcomeric thin-filament structure. Changes in the spontaneous beating of cardiomyocytes corresponding with myofibrillar degeneration were apparent using differential interference contrast video microscopy. After finding induction of kinase activity by doxorubicin in cultured cardiomyocytes, the protective effects of specific inhibitors of kinase activity were assessed for their ability to inhibit doxorubicin-induced myofibrillar break-down. Doxorubicin-induced changes appeared similar to the degeneration observed after treatment with a protein kinase activator (phorbol 12-myristate 13-acetate) or a serine-threonine protein phosphatase inhibitor (okadaic acid). Collectively, these results indicate that activation of protein kinase is an important event in the initiation of myofibrillar degeneration by doxorubicin. Further analyses of myofibrillar proteins with respect to biochemical modifications will be necessary to determine if phosphorylation events transmit signal(s) to initiate degeneration.
在适应性心脏反应（即肥大）以及具有心脏毒性副作用的抗肿瘤药物（即阿霉素）的化疗应用中，均观察到肌丝的丧失。了解退行性过程是确定限制与慢性心脏病或长期化疗相关的心肌病变化方法的先决条件。然而，对于引发退行性过程的具体事件和分子变化知之甚少。为了研究这个过程，用阿霉素处理新生大鼠心肌细胞，通过荧光共聚焦显微镜观察到其诱导了快速且广泛的细肌丝退化。这表明肌节细肌丝结构的恶化。使用微分干涉对比视频显微镜可以明显观察到与肌原纤维退化相对应的心肌细胞自发搏动的变化。在培养的心肌细胞中发现阿霉素诱导激酶活性后，评估了激酶活性特异性抑制剂对抑制阿霉素诱导的肌原纤维分解的保护作用。阿霉素诱导的变化似乎类似于用蛋白激酶激活剂（佛波醇12 - 肉豆蔻酸酯13 - 乙酸酯）或丝氨酸 - 苏氨酸蛋白磷酸酶抑制剂（冈田酸）处理后观察到的退化。总体而言，这些结果表明蛋白激酶的激活是阿霉素引发肌原纤维退化的重要事件。关于生化修饰对肌原纤维蛋白进行进一步分析，对于确定磷酸化事件是否传递信号以引发退化是必要的。
