Adriamycin depresses in vivo and in vitro phosphatidylethanolamine N-methylation in rat heart sarcolemma
Adriamycin depresses in vivo and in vitro phosphatidylethanolamine N-methylation in rat heart sarcolemma
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DOI：
10.1023/a:1006805229758
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发表时间：
1997-11-01
影响因子：
4.3
通讯作者：
Singal, PK
中科院分区：
文献类型：
--
作者：
Iliskovic, N;Panagia, V;Singal, PK
阿霉素是一种有效的抗癌化疗药物，会引起隐匿性和迟发性心脏毒性。不同的亚细胞异常，包括肌膜 (SL) 中钙转运的变化以及肾上腺素能系统的下调，已被证明与这种心肌病的发生有关。由于这两种活性均受到磷脂甲基化的影响，因此检查了阿霉素对 SL 磷脂酰乙醇胺 N-甲基转移酶的三个催化位点的影响。大鼠在两周内接受累积剂量的阿霉素（15 mg/kg），并在三周后进行检查。注射媒介物的动物作为对照。阿霉素组出现呼吸困难、高死亡率、腹水、主动脉和左心室收缩压降低、左心室舒张末压升高。阿霉素心肌病典型的心肌细胞损伤，即肌小管肿胀、空泡形成和肌原纤维脱落，也很明显。使用放射性标记的 S-腺苷-L-甲硫氨酸作为供体的 SL 磷脂酰乙醇胺中的总甲基掺入在 3 周组中在催化位点 II 和 III 处显着降低。甲基化中间体、磷脂酰-N-单甲基乙醇胺和磷脂酰-N,N-二甲基乙醇胺以及磷脂酰胆碱 (PC) 的产量减少。当从未经处理的心脏分离的SL在体外暴露于不同浓度（10、100和1000μM）的阿霉素时，还注意到磷脂酰乙醇胺N-甲基化的抑制。磷脂酰乙醇胺 N-甲基化的抑制似乎是由阿霉素诱导的氧化应激增加介导的，并且可能有助于与这种心肌病相关的亚细胞变化的发病机制。
Adriamycin, an effective anticancer chemotherapeutic agent, causes an insidious and delayed cardiotoxicity. Different subcellular abnormalities including calcium transport changes in the sarcolemma (SL) as well as downregulation of the adrenergic system have been shown to be associated with the development of this cardiomyopathy. Since both of these activities are influenced by phospholipid methylation, effects of adriamycin on the three catalytic sites of SL phosphatidylethanolamine N-methyltransferase were examined. Rats were administered with a cumulative dose of adriamycin (15 mg/kg) over 2 weeks and examined after 3 weeks. Vehicle injected animals served as controls. Dyspnea, high mortality rate, ascites and decrease in aortic and left ventricular systolic pressure, as well as increase in left ventricular end diastolic pressure were seen in the adriamycin group. Myocardial cell damage typical of adriamycin cardiomyopathy, i.e. sarcotubular swelling, vacuolization and myofibrillar drop-out, was also apparent. Total methyl group incorporation into SL phosphatidylethanolamine using radiolabeled S-adenosyl-L-methionine as the donor was significantly depressed in the 3 week group at catalytic sites II and III. Decreased production of methylated intermediates, phosphatidyl-N-monomethylethanolamine and phosphatidyl-N,N-dimethyiethanolamine as well as phosphatidylcholine (PC) was seen. Depression of phosphatidylethanolamine N-methylation was also noticed when SL, isolated from untreated hearts, was exposed in vitro to different concentrations (10, 100 and 1000 mu M) of adriamycin. Inhibition of phosphatidylethanolamine N-methylation appears to be mediated by adriamycin-induced increase in the oxidative stress and may contribute in the pathogenesis of subcellular changes associated with this cardiomyopathy.