Arai M, Tomaru K, Takizawa T, Sekiguchi K, Yokoyama T, Suzuki T, Nagai R
Second Department of Internal Medicine, Gunma University School of Medicine, Japan.
J Mol Cell Cardiol. 1998 Feb;30(2):243-54. doi: 10.1006/jmcc.1997.0588.
The clinical utility of doxorubicin, an antineoplastic agent, is limited by its cardiotoxicity. Our objective was to determine whether expression of genes encoding proteins that affect Ca2+ homeostasis were altered in the hearts of rabbits chronically treated with doxorubicin. Twelve male New Zealand white rabbits received an injection of doxorubicin (2.5 mg/kg i.v.) once a week for 8 weeks. Eight rabbits were similarly injected with saline as controls. The cardiac function of both groups was evaluated 8 weeks after the final injection, as were the levels of expression of mRNA for Ca2+ transport proteins in the sarcoplasmic reticulum and plasma membrane. The amount of the sarcoplasmic reticulum Ca2+-ATPase and the Ca2+ uptake capacity of the protein were also quantitated. Cardiac output was significantly decreased in the doxorubicin-treated group (71+/-21 ml/min, P<0.05) compared with the control group (118+/-15 ml/min). The mRNA levels for the sarcoplasmic reticulum proteins were significantly diminished in the doxorubicin-treated hearts: ryanodine receptor-2 (relative expression level compared with controls, 0.35+/-0.13, P<0.01), sarcoplasmic reticulum Ca2+-ATPase (0.56+/-0.13, P<0.01), phospholamban (0.62+/-0.20, P<0.01) and cardiac calsequestrin (0. 57+/-0.26, P<0.01). In addition, both relative amount of sarcoplasmic reticulum Ca2+-ATPase protein (doxorubicin-treated group, 69+/-17% of control, P<0.01) and the Ca2+ uptake capacity (46. 9+/-9.8 nmol Ca2+/mg protein-5 min in doxorubicin group v 63.2+/-10. 4 in the control group, P<0.01) were concomitantly decreased with its mRNA expression level. Conversely, the mRNA levels for the plasma membrane proteins did not differ from those of control rabbits: the dihydropyridine receptor (relative expression level, 1. 03+/-0.30, N.S.), plasma membrane Ca2+-ATPase (0.93+/-0.33, N.S.) and the Na+/Ca2+ exchanger (0.87+/-0.34, N.S.). These findings suggest that a selective decrease in mRNA expression for sarcoplasmic reticulum Ca2+ transport proteins is responsible for the impaired Ca2+ handling, and thus, for the reduced cardiac function seen in the cardiomyopathy induced in rabbits by the long-term treatment with doxorubicin.
抗肿瘤药物阿霉素的临床应用因心脏毒性而受到限制。我们的目的是确定长期用阿霉素治疗的兔心脏中，编码影响Ca2+稳态的蛋白质的基因表达是否发生改变。12只雄性新西兰白兔每周静脉注射一次阿霉素（2.5mg/kg），共8周。8只兔子同样注射生理盐水作为对照。最后一次注射8周后评估两组的心脏功能，以及肌浆网和质膜中Ca2+转运蛋白的mRNA表达水平。同时对肌浆网Ca2+-ATP酶的量及其蛋白质的Ca2+摄取能力进行定量。与对照组（118±15ml/min）相比，阿霉素治疗组的心输出量显著降低（71±21ml/min，P<0.05）。阿霉素治疗的心脏中，肌浆网蛋白的mRNA水平显著降低：兰尼碱受体-2（与对照组相比的相对表达水平，0.35±0.13，P<0.01）、肌浆网Ca2+-ATP酶（0.56±0.13，P<0.01）、受磷蛋白（0.62±0.20，P<0.01）和心肌钙结合蛋白（0.57±0.26，P<0.01）。此外，肌浆网Ca2+-ATP酶蛋白的相对量（阿霉素治疗组为对照组的69±17%，P<0.01）和Ca2+摄取能力（阿霉素组为46.9±9.8nmol Ca2+/mg蛋白-5min，对照组为63.2±10.4，P<0.01）均随其mRNA表达水平而同时降低。相反，质膜蛋白的mRNA水平与对照兔无差异：二氢吡啶受体（相对表达水平，1.03±0.30，无显著性差异）、质膜Ca2+-ATP酶（0.93±0.33，无显著性差异）和Na+/Ca2+交换体（0.87±0.34，无显著性差异）。这些发现表明，肌浆网Ca2+转运蛋白mRNA表达的选择性降低是Ca2+处理受损的原因，因此也是长期用阿霉素诱导的兔心肌病中心脏功能降低的原因。
