HDAC6 inhibition protects cardiomyocytes against doxorubicin-induced acute damage by improving α-tubulin acetylation
HDAC6 inhibition protects cardiomyocytes against doxorubicin-induced acute damage by improving α-tubulin acetylation
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HDAC6 抑制通过改善 α-微管蛋白乙酰化保护心肌细胞免受阿霉素诱导的急性损伤
DOI：
10.1016/j.yjmcc.2018.10.007
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发表时间：
2018
影响因子：
5
通讯作者：
Yichun Zhu
中科院分区：
文献类型：
--
作者：
Rui Song;Yurong Yang;Han Lei;Guangxue Wang;Yong Huang;Wenlong Xue;Yinfang Wang;Lingling Yao;Yichun Zhu
多柔比星（Dox）是一种有效的抗肿瘤药物，但因其心脏毒性而限制了其应用。组蛋白去乙酰化酶6（HDAC 6）已被证明参与心肌病，然而，其在Dox诱导的心脏损伤中的作用在很大程度上是未知的。在这项研究中，我们首先旨在确定HDAC 6在Dox诱导的心肌病中的作用。免疫印迹结果显示，Dox在体内外均能提高HDAC 6蛋白水平和活性，降低α-微管蛋白乙酰化水平。HDAC 6基因敲除（HDAC 6 −/−）小鼠通过超声心动图监测的心脏功能保护表现出明显的抗Dox心脏毒性，并且这种保护作用可被降低α-微管蛋白乙酰化的药物Nocodazole逆转。进一步的机制研究表明，Nocodazole和秋水仙碱通过降低α-tubulin乙酰化水平，部分抑制了心肌细胞线粒体功能和自噬流量的改善。为将本研究成果转化为临床应用，我们进一步探讨HDAC 6抑制剂与Dox联合应用对肿瘤及心功能的影响。结果表明，Tubastatin A，一种HDAC 6选择性抑制剂，保护免受Dox诱导的急性心肌病，而不影响Dox抑制MDA-MB-231皮下肿瘤生长的效果。这些发现表明，通过与HDAC 6选择性抑制剂联合使用，Dox是一种新的癌症治疗方法。
Doxorubicin (Dox) is an efficacious antineoplastic drug but is limited used for its cardiotoxicity. Histone Deacetylase 6 (HDAC6) has been indicated to participate in cardiomyopathies, however, its role in Dox-induced cardiac injury is largely unknown. In this study, we firstly aimed to determine the role of HDAC6 in Dox-induced cardiomyopathy. Immunoblotting revealed that Dox increased HDAC6 protein level and activity and decreased α-tubulin acetylation level in vitro and vivo. HDAC6 knockout (HDAC6−/−) mice showed obvious anti-Dox cardiotoxicity by conserved cardiac function monitored by echocardiography and the protection was reversed by Nocodazole, one drug lowering α-tubulin acetylation. Further mechanism investigation showed that improvement of mitochondria function and autophagy flux was partially inhibited by Nocodazole and Colchicine which lowers α-tubulin acetylation in neonatal rat cardiac myocytes. Aiming at transforming this research to clinical application, we then explored the effect of combined utilization of HDAC6 inhibitor and Dox on tumour and cardiac function. Results showed that Tubastatin A, one HDAC6 selective inhibitor, protected against Dox-induced acute cardiomyopathy without influencing the effect of Dox on inhibiting MDA-MB-231 subcutaneous tumour growth. These findings suggest a new treatment for cancer with Dox by combined utilization with HDAC6 selective inhibitors.