miR-21-5p prevents doxorubicin-induced cardiomyopathy by downregulating BTG2.
miR-21-5p prevents doxorubicin-induced cardiomyopathy by downregulating BTG2.
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DOI：
10.1016/j.heliyon.2023.e15451
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发表时间：
2023-05
期刊：
影响因子：
4
通讯作者：
Qiu, Yan
中科院分区：
文献类型：
--
作者：
Wang, Qingwei;Jiang, Fei;Zhao, Chenglin;Song, Jiaxin;Hu, Meiyu;Lv, Yicheng;Duan, Yi;Fang, Wenqian;Ding, Rongjing;Qiu, Yan
心肌细胞凋亡是阿霉素（DOX）诱导心肌病的主要机制之一。据报道，microRNA-21- 5 p（miR-21- 5 p）可减轻缺血诱导的心肌细胞凋亡和心脏损伤。然而，据我们所知，miR-21- 5 p在DOX诱导的心肌病中的功能作用尚不清楚。在这项研究中，我们探讨了miR-21- 5 p在DOX诱导的心脏损伤中的作用。采用实时荧光定量聚合酶链反应（qRT-PCR）检测miR-21- 5 p的表达水平。采用双荧光素酶报告基因检测技术验证miR-21- 5 p的潜在靶基因。TUNEL法检测细胞凋亡率。Western blot检测Bax、Bcl-2、Caspase 3、cleaved-Caspase 3和BTG 2蛋白表达水平。对于动物研究，用AAV 9-miR-21- 5 p或AAV 9-空病毒注射小鼠，并通过腹膜内施用以每周5 mg/kg的剂量用DOX处理。在DOX治疗4周后，对小鼠进行超声心动图以测量左心室射血分数（EF）和缩短分数（FS）。结果显示，miR-21- 5 p在DOX处理的原代心肌细胞和小鼠心脏组织中均上调。有趣的是，增加miR-21- 5 p表达抑制DOX诱导的心肌细胞凋亡和氧化应激，而减少miR-21- 5 p表达促进心肌细胞凋亡和氧化应激。此外，心脏过表达miR-21- 5 p可保护免受DOX诱导的心脏损伤。机制研究表明BTG 2是miR-21- 5 p的靶基因。miR-21- 5 p的抗凋亡作用可被BTG 2过表达所抑制。相反，抑制BTG 2挽救了miR-21- 5 p抑制剂的促凋亡作用。总之，我们的研究表明，miR-21- 5 p可以通过下调BTG 2来预防DOX诱导的心肌病。
Cardiomyocyte apoptosis has been characterized as one of the major mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy. MicroRNA-21-5p (miR-21-5p) was reported to mitigate ischemia-induced cardiomyocyte apoptosis and cardiac injury. However, to our knowledge, the functional role of miR-21-5p in DOX-induced cardiomyopathy is unclear. In this study, we explored the role of miR-21-5p in DOX-induced cardiac injury. The expression level of miR-21-5p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Dual luciferase reporter assay was used to verify the potential target gene of miR-21-5p. The apoptosis rate of NRCMs was detected by TUNEL staining assay. Western blot analysis was used to detect the protein expression levels of Bax, Bcl-2, Caspase3, cleaved-Caspase3 and BTG2. For animal studies, mice were injected with AAV9-miR-21-5p or AAV9-Empty viruses, and treated with DOX at a dose of 5 mg/kg per week through intraperitoneally administration. After 4 weeks of DOX treatment, mice were subjected to echocardiography to measure the left ventricular ejection fraction (EF) and fractional shortening (FS). Results showed that miR-21-5p was upregulated in both DOX-treated primary cardiomyocytes and mouse heart tissues. Interestingly, enhanced miR-21-5p expression inhibited DOX-induced cardiomyocyte apoptosis and oxidative stress, while decreased miR-21-5p expression promoted cardiomyocyte apoptosis and oxidative stress. Furthermore, cardiac overexpression of miR-21-5p protected against DOX-induced cardiac injury. The mechanistic study indicated that BTG2 was a target gene of miR-21-5p. The anti-apoptotic effect of miR-21-5p could be inhibited by BTG2 overexpression. Conversely, inhibition of BTG2 rescued the pro-apoptotic effect of miR-21-5p inhibitor. Taken together, our study showed that miR-21-5p could prevent DOX-induced cardiomyopathy by downregulating BTG2.
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