Sodium nitroprusside induces cell death and cytoskeleton degradation in adult rat cardiomyocytes in vitro: implications for anthracycline-induced cardiotoxicity
Sodium nitroprusside induces cell death and cytoskeleton degradation in adult rat cardiomyocytes in vitro: implications for anthracycline-induced cardiotoxicity
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DOI：
10.4081/ejh.2012.e15
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发表时间：
2012-01-01
影响因子：
2
通讯作者：
Zuppinger, C.
中科院分区：
文献类型：
--
作者：
Chiusa, M.;Timolati, F.;Zuppinger, C.
硝普钠（SNP）在临床上用作速效血管扩张剂，在实验模型中用作一氧化氮（NO）供体。高浓度的NO已被报道诱导心脏毒性作用，包括通过形成活性氧而引起的细胞凋亡。因此，我们研究了SNP对长期培养的成年大鼠心肌细胞在治疗后不同时间点的肌原纤维细胞骨架、收缩力和细胞死亡的影响。我们的研究结果表明，SNP治疗首先导致细胞骨架降解的逐渐增加，其标志是肌动蛋白标记的丧失和肌节结构的碎片化，随后出现TUNEL阳性细胞核。已经较低剂量的SNP降低了以2 Hz起搏的心肌细胞的收缩性，而不改变细胞内钙浓度。培养细胞的超微结构分析表明线粒体的变化和解体的肌节排列。SNP在心肌细胞中的这些不良作用使人联想到蒽环类药物诱导的心脏毒性，其还涉及NO的失调，其结果是肌原纤维降解和最终细胞死亡。抑制导致反应性NO产物产生的途径或其中和作用可能对SNP和蒽环类药物诱导的心脏毒性具有显著的治疗益处。
Sodium nitroprusside (SNP) is used clinically as a rapid-acting vasodilator and in experimental models as donor of nitric oxide (NO). High concentrations of NO have been reported to induce cardiotoxic effects including apoptosis by the formation of reactive oxygen species. We have therefore investigated effects of SNP on the myofibrillar cytoskeleton, contractility and cell death in long-term cultured adult rat cardiomyocytes at different time points after treatment. Our results show, that SNP treatment at first results in a gradual increase of cytoskeleton degradation marked by the loss of actin labeling and fragmentation of sarcomeric structure, followed by the appearance of TUNEL-positive nuclei. Already lower doses of SNP decreased contractility of cardiomyocytes paced at 2 Hz without changes of intracellular calcium concentration. Ultrastructural analysis of the cultured cells demonstrated mitochondrial changes and disintegration of sarcomeric alignment. These adverse effects of SNP in cardiomyocytes were reminiscent of anthracycline-induced cardiotoxicity, which also involves a dysregulation of NO with the consequence of myofibrillar degradation and ultimately cell death. An inhibition of the path-ways leading to the generation of reactive NO products, or their neutralization, may be of significant therapeutic benefit for both SNP and anthracycline-induced cardiotoxicity.