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  • 郭显,史承勇,王文生,余慧,李攀,赵仙先.微RNA-21通过激活沉默信息调控因子1信号通路缓解多柔比星心肌毒性[J].第二军医大学学报,2019,40(4):386-393    [点击复制]
  • GUO Xian,SHI Cheng-yong,WANG Wen-sheng,YU Hui,LI Pan,ZHAO Xian-xian.MicroRNA-21 attenuates doxorubicin-induced cardiotoxicity by activating silent information regulator 1 signaling pathway[J].Acad J Sec Mil Med Univ,2019,40(4):386-393   [点击复制]
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微RNA-21通过激活沉默信息调控因子1信号通路缓解多柔比星心肌毒性
郭显1,2,史承勇1,王文生2,余慧1,李攀1*,赵仙先1*
0
(1. 海军军医大学(第二军医大学)长海医院心血管内科, 上海 200433;
2. 解放军95247部队医院, 惠州 516259
*通信作者)
摘要:
目的 探讨微RNA-21(miR-21)能否减轻多柔比星(DOX)心肌毒性,并阐明沉默信息调控因子1(SIRT1)信号通路是否介导其作用。方法 用DOX(1 μmol/L)处理大鼠原代心肌细胞构建DOX心肌毒性模型。将心肌细胞分为8组:对照组、miR-21组、miR-21抑制剂组、DOX组、miR-21+DOX组、miR-21抑制剂+DOX组、Sirtinol+miR-21+DOX组、Sirtinol+DOX组,miR-21 mimics、miR-21抑制剂和Sirtinol(SIRT1抑制剂)分别于DOX处理前24 h加入细胞培养液中。DOX处理24 h后检测心肌细胞的细胞活力、凋亡率、凋亡相关蛋白和SIRT1信号通路表达情况。结果 与对照组相比,DOX处理24 h后心肌细胞活力降低,Bcl-2和SIRT1表达量降低,而Bax和cleaved Caspase-3表达量增加,细胞凋亡率增高,差异均有统计学意义(P<0.05)。与DOX组相比,miR-21可明显提高心肌细胞活力,上调Bcl-2和SIRT1表达,下调Bax和cleaved Caspase-3表达,降低细胞凋亡率,差异均有统计学意义(P<0.05)。抑制SIRT1信号通路可削弱miR-21对心肌细胞的保护作用(P<0.05)。结论 miR-21可通过激活SIRT1信号通路抑制心肌细胞凋亡,提高细胞活力,缓解DOX心肌毒性。
关键词:  多柔比星  心肌毒性  微RNA-21  沉默信息调控因子1  细胞凋亡
DOI:10.16781/j.0258-879x.2019.04.0386
投稿时间:2018-12-04修订日期:2019-03-14
基金项目:国家自然科学基金(81570208).
MicroRNA-21 attenuates doxorubicin-induced cardiotoxicity by activating silent information regulator 1 signaling pathway
GUO Xian1,2,SHI Cheng-yong1,WANG Wen-sheng2,YU Hui1,LI Pan1*,ZHAO Xian-xian1*
(1. Department of Cardiovasology, Changhai Hospital, Naval Medical University(Second Military Medical University), Shanghai 200433, China;
2. Hospital of PLA No. 95247 Troop, Huizhou 516259, Guangdong, China
*Corresponding authors)
Abstract:
Objective To explore whether microR-21 (miR-21) can alleviate doxorubicin (DOX)-induced cardiotoxicity and whether silent information regulator 1 (SIRT1) signaling pathway mediates the roles. Methods Neonatal rat cardiac myocytes were treated with DOX (1 μmol/L) to induce DOX myocardial toxicity model. The cardiomyocytes were randomized into 8 groups:control group, miR-21 group, miR-21 inhibitor group, DOX group, miR-21+DOX group, miR-21 inhibitor+DOX group, Sirtinol+miR-21+DOX group and Sirtinol+DOX group. The miR-21 mimics, miR-21 inhibitors and Sirtinol (SIRT1 inhibitor) were given at 24 h before DOX treatment. After treatment with DOX for 24 h, the cell viability, apoptosis rate, and the expression levels of apoptosis-related proteins and SIRT1 signaling pathway were detected. Results Compared with the control group, the cell viability, and the expression levels of Bcl-2 and SIRT1 were significantly decreased in the cardiomyocytes after treatment with DOX for 24 h, while the expression levels of Bax and cleaved Caspase-3, and apoptotic rate were significantly increased (P<0.05). Compared with the DOX group, miR-21 significantly increased cell viability and the expression levels of Bcl-2 and SIRT1, and significantly decreased the expression levels of Bax and cleaved Caspase-3 and apoptotic rate (P<0.05). Inhibiting SIRT1 signaling pathway could significantly weaken the protective effect of miR-21 on cardiomyocytes (P<0.05). Conclusion miR-21 can inhibit cardiomyocyte apoptosis, increase cell viability and alleviate DOX-induced cardiotoxicity by activating SIRT1 signaling pathway.
Key words:  doxorubicin  cardiotoxicity  miR-21  silent information regulator 1  cell apoptosis