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MiR-15b-5p is Involved in Doxorubicin-Induced Cardiotoxicity via Inhibiting Bmpr1a Signal in H9c2 Cardiomyocyte

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Abstract

The wide use of anthracyclines represented by doxorubicin (DOX) has benefited cancer patients, yet the clinical application is limited due to its cardiotoxicity. Although numerous evidences have supported a role of microRNAs (miRNAs) in DOX-induced myocardial damage, the exact etiology and pathogenesis remain largely obscure. In this study, we focused on the role of miR-15b-5p in DOX-induced cardiotoxicity. We employed a public miRNA and gene microarray to screen differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) in rat cardiomyocytes, and 33 DEMs including miR-15b-5p and 237 DEGs including Bmpr1a and Gata4 were identified. The Gene ontology (GO) and pathway enrichment analysis of 237 DEGs indicated that the DEGs were mainly enriched in heart development and ALK pathway in cardiomyocyte which included the main receptor Bmpr1a and transcription factor Gata4. The up-regulated miR-15b-5p and down-regulated Bmpr1a and Gata4 mRNA expressions were further validated in H9c2 cardiomyocytes exposed to DOX. Moreover, the results showed overexpression of miR-15b-5p or inhibition of Bmpr1a may enhance the DOX-induced apoptosis, oxidative stress and mitochondria damage in H9c2 cardiomyocytes. The Bmpr1a was suggested as a potential target of miR-15b-5p by bioinformatics prediction. We further verified the negatively regulatory effect of miR-15b-5p on Bmpr1a signaling. Moreover, we also confirmed that overexpression of miR-15b-5p may exacerbate the DOX-induced apoptosis of H9c2 cardiomyocytes by affecting the protein expression ratio of Bcl-2/Bax and Akt activation, while this pro-apoptotic effect was able to be suppressed by Bmpr1a agonist. Collectively, the results suggest that miR-15b-5p is likely involved in doxorubicin-induced cardiotoxicity via inhibiting Bmpr1a signaling in H9c2 cardiomyocytes. Our study provides a novel insight for investigating DOX-induced cardiotoxicity.

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Authors and Affiliations

  1. Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Dongxia North Road, Shantou, 515041, Guangdong, People’s Republic of China

    Guo-xing Wan, Lan Cheng, Hai-lun Qin, Yun-zhang Zhang, Ling-yu Wang & Yong-gang Zhang

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  1. Guo-xing Wan
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  2. Lan Cheng
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  3. Hai-lun Qin
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  4. Yun-zhang Zhang
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  5. Ling-yu Wang
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  6. Yong-gang Zhang
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Correspondence to Yong-gang Zhang.

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The authors declare that they have no conflict of interest with respect to the research, authorship, and/or publication of this article.

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Wan, Gx., Cheng, L., Qin, Hl. et al. MiR-15b-5p is Involved in Doxorubicin-Induced Cardiotoxicity via Inhibiting Bmpr1a Signal in H9c2 Cardiomyocyte. Cardiovasc Toxicol 19, 264–275 (2019). https://doi.org/10.1007/s12012-018-9495-6

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  • DOI: https://doi.org/10.1007/s12012-018-9495-6

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