MicroRNA-155 Promotes Myocardial Infarction-Induced Apoptosis by Targeting RNA-Binding Protein QKI
MicroRNA-155 Promotes Myocardial Infarction-Induced Apoptosis by Targeting RNA-Binding Protein QKI
复制标题
微小RNA - 155通过靶向RNA结合蛋白QKI促进心肌梗死诱导的细胞凋亡
DOI：
10.1155/2019/4579806
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发表时间：
2019-01-01
影响因子：
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通讯作者：
Du, Zhi-Min
中科院分区：
文献类型：
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作者：
Guo, Jing;Liu, Hui-Bin;Du, Zhi-Min
急性心肌梗死（AMI）是全球范围内猝死的主要原因。MicroRNA-155（miR-155）已被报道在多种疾病模型中靶向抗凋亡基因，但miR-155在响应MI损伤中的功能作用需要进一步研究。本研究探讨了miR-155在心肌缺血损伤中的作用。TUNEL法和流式细胞术检测细胞凋亡。Western blot检测Bcl-2、XIAP、Bax和caspase-3蛋白表达。使用qRT-PCR定量miRNA水平。我们发现，miR-155在MI小鼠心脏和过氧化氢（H2 O2）诱导的新生大鼠心室心肌细胞（NRVM）损伤中动态升高。响应于H2 O2，使用AMO-155（反义抑制剂寡脱氧核糖核苷酸）沉默miR-155显著增加细胞活力并减少细胞凋亡。此外，AMO-155逆转了H2 O2诱导的Bcl-2和XIAP下调以及Bax和切割的caspase-3上调。进一步的研究表明，AMO-155导致H2 O2诱导的JC-1标记的单体细胞数量减少。此外，AMO-155显著减小MI小鼠心脏中的梗死面积，改善受损的心脏功能，并显著降低凋亡细胞百分比。通过生物信息学分析预测RNA结合蛋白Quaking（QKI）为miR-155的靶基因，AMO-155可减弱H2 O2处理的心肌细胞和MI小鼠心脏中QKI的下调。通过siRNA敲低QKI消除了AMO-155的抗凋亡作用。总之，miR-155在MI心脏和NRVM中响应于H2 O2应激而上调，并且下调miR-155保护心肌细胞免于凋亡。从机制上讲，这可能是由于QKI信号通路的抑制。
Acute myocardial infarction (AMI) is the leading cause of sudden death worldwide. MicroRNA-155 (miR-155) has been reported to target antiapoptotic genes in various diseases models, but the functional role of miR-155 in response to MI injury needs further investigations. This study investigated the role of miR-155 in myocardial ischemia injury. TUNEL and flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect protein expressions of Bcl-2, XIAP, Bax, and caspase-3. qRT-PCR was used to quantify miRNA levels. We showed that miR-155 was dynamically elevated in murine hearts subjected to MI and in neonatal rat ventricular cardiomyocyte (NRVM) injury induced by hydrogen peroxide (H2O2). In response to H2O2, the silencing of miR-155 using AMO-155 (antisense inhibitor oligodeoxyribonucleotides) significantly increased cell viability and reduced cell apoptosis. Moreover, AMO-155 reversed the H2O2-induced downregulation of Bcl-2 and XIAP and upregulation of Bax and cleaved-caspase-3. Further study revealed that AMO-155 resulted in a decrease of H2O2 -induced JC-1-labelled monomeric cell number. In addition, AMO-155 markedly decreased infarct size, ameliorated impaired cardiac function, and significantly reduced apoptotic cell percentages in MI mice heart. The RNA-binding protein Quaking (QKI) was predicted as a target gene of miR-155 through bioinformatic analysis, and AMO-155 attenuated the downregulation of QKI in H2O2-treated cardiomyocytes and MI mice heart. Knockdown of QKI by siRNA abolished the antiapoptotic effects of AMO-155. Taken together, miR-155 is upregulated in the MI heart and NRVMs in response to H2O2 stress, and downregulating of miR-155 protects cardiomyocytes against apoptosis. Mechanistically, it is probably due to the repression of QKI signaling pathway.