LCZ696 improves cardiac function via alleviating Drpl-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy
LCZ696 improves cardiac function via alleviating Drpl-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy
复制标题
LCZ696 通过减轻阿霉素诱导的扩张型心肌病小鼠 Drpl 介导的线粒体功能障碍来改善心脏功能
DOI：
10.1016/j.yjmcc.2017.06.003
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发表时间：
2017-07-01
影响因子：
5
通讯作者：
Ge, Junbo
中科院分区：
文献类型：
--
作者：
Xia, Yan;Chen, Zhangwei;Ge, Junbo
目的：LCZ 696是一种新型的血管紧张素受体脑啡肽酶抑制剂，可有效治疗心力衰竭患者。多柔比星（DOX）是一种有效的抗肿瘤药物，但其心脏毒性限制了其临床应用。在这项研究中，我们的目的是确定LCZ 696对DOX诱导的心肌病在小鼠和体外的影响，并探讨相关的机制集中在裂变蛋白动力蛋白相关蛋白1（Drpl）。方法和结果：在人体研究中，我们发现心肌裂变蛋白Drpl的表达和其ser 616磷酸化显着增加扩张型心肌病（DCM）患者。将雄性Balb/c小鼠和H9 c2心肌细胞随机分为三组：生理盐水、DOX、DOX + LCZ 696。LCZ 696可显著改善DOX刺激后小鼠心功能下降、线粒体形态紊乱、线粒体呼吸复合物I活性降低和三磷酸腺苷（ATP）含量降低。分裂蛋白Drpl及其ser 616磷酸化也在DOX后增加，并且可以被LCZ 696降低。在体外，增加的心肌细胞凋亡，D 0X刺激后的Drpl ser 616磷酸化可被LCZ 696或Drpl特异性抑制剂Midivi-1显著减弱。结论：LCZ 696对阿霉素诱导的H9 c2细胞心肌损伤的保护作用至少部分与减轻Drpl介导的线粒体功能障碍有关。(C)2017爱思唯尔有限公司版权所有
Aims: LCZ696, a novel angiotensin receptor neprilysin inhibitor, is effective in treating heart failure patients. Doxorubicin (DOX) is an effective antitumor medication but the cardiotoxicity limited its clinical use. In this study, we aimed to determine the effect of LCZ696 on DOX-induced cardiomyopathy in mice and in vitro and to explore related mechanisms focusing on fission protein dynamin-related protein 1 (Drpl).Methods and results: In human study, we found that myocardial fission protein Drpl expression and its ser 616 phosphorylation were significantly increased in dilated cardiomyopathy (DCM) patients. Male Balb/c mice and H9c2 cardiomyocytes were randomized into three groups: saline, DOX, DOX plus LCZ696. Reduced cardiac function, mitochondrial morphology disturbance, reduced activity of mitochondria] respiration complex I and lowered adenosine triphosphate (ATP) content were detected post DOX stimulation in mice, which could be significantly improved by LCZ696. Fission protein Drpl and its ser 616 phosphorylation were also increased post DOX and which could be reduced by LCZ696. In vitro, increased cardiomyocyte apoptosis, Drpl ser 616 phosphorylation post DOX stimulation could be significantly attenuated by LCZ696 or Drpl specific inhibitor Midivi-1. Furthermore, over-expression of Drpl abrogated the protection effect of LCZ696 against DOX-induced cardiotoxicity in H9c2 cells.Conclusion: The protective effect of LCZ696 against DOX-induced cardiac dysfunction is at least partly associated with alleviating Drpl-mediated mitochondrial dysfunction. (C) 2017 Elsevier Ltd. All rights reserved.