促红细胞生成素对阿霉素诱导的心肌病心脏功能障碍的预防作用。
Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy.
作者信息
Li Longhu, Takemura Genzou, Li Yiwen, Miyata Shusaku, Esaki Masayasu, Okada Hideshi, Kanamori Hiromitsu, Khai Ngin Cin, Maruyama Rumi, Ogino Atsushi, Minatoguchi Shinya, Fujiwara Takako, Fujiwara Hisayoshi
机构信息
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu 501-1194, Japan.
出版信息
Circulation. 2006 Jan 31;113(4):535-43. doi: 10.1161/CIRCULATIONAHA.105.568402.
BACKGROUND
Doxorubicin is a highly effective antineoplastic drug, but its clinical use is limited by its adverse side effects on the heart. We investigated possible protective effects of erythropoietin against doxorubicin-induced cardiomyopathy.
METHODS AND RESULTS
Cardiomyopathy was induced in mice by a single intraperitoneal injection of doxorubicin (15 mg/kg). In some cases, human recombinant erythropoietin (5000 U/kg) was started simultaneously. Two weeks later, left ventricular dilatation and dysfunction were apparent in mice given doxorubicin but were significantly attenuated by erythropoietin treatment. Erythropoietin also protected hearts against doxorubicin-induced cardiomyocyte atrophy and degeneration, myocardial fibrosis, inflammatory cell infiltration, and downregulation of expression of GATA-4 and 3 sarcomeric proteins, myosin heavy chain, troponin I, and desmin. Cyclooxygenase-2 expression was upregulated in doxorubicin-treated hearts, and that, too, was attenuated by erythropoietin. No doxorubicin-induced apoptotic effects were seen, nor were any changes seen in the expression of tumor necrosis factor-alpha or transforming growth factor-beta1. Antiatrophic and GATA-4 restoring effects of erythropoietin were demonstrated in the in vitro experiments with cultured cardiomyocytes exposed to doxorubicin, which indicated the direct cardioprotective effects of erythropoietin beyond erythropoiesis. Cardiac erythropoietin receptor expression was downregulated in doxorubicin-induced cardiomyopathy but was restored by erythropoietin. Among the downstream mediators of erythropoietin receptor signaling, activation of extracellular signal-regulated kinase was reduced by doxorubicin but restored by erythropoietin. By contrast, erythropoietin was ineffective when administered after cardiac dysfunction was established in the chronic stage.
CONCLUSIONS
The present study indicates a protective effect of erythropoietin against doxorubicin-induced cardiomyopathy.
背景
阿霉素是一种高效的抗肿瘤药物，但其临床应用因对心脏的不良副作用而受到限制。我们研究了促红细胞生成素对阿霉素诱导的心肌病的可能保护作用。
方法与结果
通过单次腹腔注射阿霉素（15mg/kg）诱导小鼠发生心肌病。在某些情况下，同时开始给予人重组促红细胞生成素（5000U/kg）。两周后，给予阿霉素的小鼠出现左心室扩张和功能障碍，但促红细胞生成素治疗可使其明显减轻。促红细胞生成素还可保护心脏免受阿霉素诱导的心肌细胞萎缩和变性、心肌纤维化、炎性细胞浸润以及GATA-4和3种肌节蛋白、肌球蛋白重链、肌钙蛋白I和结蛋白表达下调的影响。在阿霉素处理的心脏中，环氧合酶-2表达上调，促红细胞生成素也可使其减弱。未观察到阿霉素诱导的凋亡效应，肿瘤坏死因子-α或转化生长因子-β1的表达也未发生变化。在体外实验中，用阿霉素处理培养的心肌细胞，证实了促红细胞生成素的抗萎缩和恢复GATA-4的作用，这表明促红细胞生成素除了具有造血作用外，还具有直接的心脏保护作用。在阿霉素诱导的心肌病中，心脏促红细胞生成素受体表达下调，但促红细胞生成素可使其恢复。在促红细胞生成素受体信号的下游介质中，细胞外信号调节激酶的激活被阿霉素降低，但被促红细胞生成素恢复。相比之下，在慢性期心脏功能障碍建立后给予促红细胞生成素则无效。
结论
本研究表明促红细胞生成素对阿霉素诱导的心肌病具有保护作用。
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