Effects of ranolazine in a model of doxorubicin-induced left ventricle diastolic dysfunction
Effects of ranolazine in a model of doxorubicin-induced left ventricle diastolic dysfunction
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DOI：
10.1111/bph.13791
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发表时间：
2017-11-01
影响因子：
7.3
通讯作者：
De Angelis, Antonella
中科院分区：
文献类型：
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作者：
Cappetta, Donato;Esposito, Grazia;De Angelis, Antonella
背景与展望阿霉素是一种高效的抗癌药物，但其临床应用受到心脏毒性的阻碍。无症状性舒张功能障碍可能是阿霉素心脏毒性的最早表现。因此，有必要寻找能够干预早期表现并可能预防心脏毒性后期发展的治疗干预措施。阿霉素依赖性ROS增加可能部分解释了导致舒张功能障碍和心力衰竭发展的Ca 2+和Na+超负荷。因此，我们测试了在完成多柔比星治疗后立即给予雷诺嗪（一种晚期Na+电流的选择性阻断剂）是否可以影响舒张功能障碍并干扰功能下降的进展。实验方法Fischer 344大鼠在2周的时间内接受累积剂量为15（-1）的多柔比星。mg.kg在评估舒张功能障碍后，在接下来的4周内用雷诺嗪（80mg.kg（-1），每天）治疗动物。关键词虽然在多柔比星治疗的动物中舒张和收缩功能逐渐恶化，但雷诺嗪治疗减轻了舒张功能障碍并防止了收缩功能的恶化，降低了死亡率。雷诺嗪降低心肌NADPH氧化酶2表达和氧化/硝化应激。Na ~+/Ca ~（2+）交换器1和Na ~+-v ~（1.5）通道表达减少，肌质/内质网Ca ~（2+）-ATP酶2蛋白表达增加。此外，雷诺嗪降低阿霉素诱导的钙/钙调蛋白依赖性蛋白激酶II的过度磷酸化和氧化，并减少心肌fibrosis.CONCLUSIONS AND IMPLICATIONSRanolazine，增加钠离子内流，诱导阿霉素，改变心脏钙和钠+处理和衰减舒张功能障碍诱导阿霉素，从而防止心肌病的进展。
BACKGROUND AND PURPOSEDoxorubicin is a highly effective anticancer drug, but its clinical application is hampered by cardiotoxicity. Asymptomatic diastolic dysfunction can be the earliest manifestation of doxorubicin cardiotoxicity. Therefore, a search for therapeutic intervention that can interfere with early manifestations and possibly prevent later development of cardiotoxicity is warranted. Increased doxorubicin-dependent ROS may explain, in part, Ca2+ and Na+ overload that contributes to diastolic dysfunction and development of heart failure. Therefore, we tested whether the administration of ranolazine, a selective blocker of late Na+ current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline.EXPERIMENTAL APPROACHFischer 344 rats received a cumulative dose of doxorubicin of 15 mg.kg(-1) over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg.kg(-1), daily) for the following 4 weeks.KEY RESULTSWhile diastolic and systolic function progressively deteriorated in doxorubicin-treated animals, treatment with ranolazine relieved diastolic dysfunction and prevented worsening of systolic function, decreasing mortality. Ranolazine lowered myocardial NADPH oxidase 2 expression and oxidative/nitrative stress. Expression of the Na+/Ca2+ exchanger 1 and Na-v 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca2+/calmodulin-dependent protein kinase II, and decreased myocardial fibrosis.CONCLUSIONS AND IMPLICATIONSRanolazine, by the increased Na+ influx, induced by doxorubicin, altered cardiac Ca2+ and Na+ handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy.