Abstract
Doxorubicin (DOX) is a widely used cytotoxic drug whose application is limited by its severe side effects. Little was known regarding how to offset its side effects. Therefore this study aims to explore the role of miR-200a-3p in DOX-induced cardiotoxicity and its possible mechanism. DOX-induced myocardial injury rat models were established, which were then injected with miR-200a-3p inhibitor (miR-200a-3p suppression) to observe the effects of miR-200a-3p on cell proliferation, and apoptosis. Heart function and weights of rat models were also measured. Cardiomyocytes were induced by DOX, in which PEG3 knockdown or corresponding plasmids were transfected to assess the possible effect of PEG3 on cell activity. Dual luciferase reporter assay was applied to verify the binding of PEG3 with miR-200a-3p. Elevated levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and left ventricular end-diastolic pressure (LVEDP), as well as suppressed left ventricular systolic pressure (LVSP) and ± dp/dt max were showed in myocardial injury rat models. DOX induced myocardial injury and increased miR-200a-3p expression levels. miR-200a-3p inhibitor could partially attenuate DOX-induced cardiotoxicity in rat models, while PEG3 could regulate myocardial injury in DOX-treated cell models. miR-200a-3p, by targeting PEG3 through SIRT1/NF-κB signal pathway, regulated cell proliferation, inflammation and apoptosis of myocardiocytes. The results in current study demonstrated that miR-200a-3p regulates cell proliferation and apoptosis of cardiomyocytes by targeting PEG3 through SIRT1/NF-κB signal pathway. This result may provide a potential clue for the treatment of DOX-induced cardiotoxicity.
Similar content being viewed by others
References
Zhu, H., Luo, P., Fu, Y., Wang, J., Dai, J., Shao, J., Yang, X., Chang, L., Weng, Q., Yang, B., & He, Q. (2015). Dihydromyricetin prevents cardiotoxicity and enhances anticancer activity induced by adriamycin. Oncotarget, 6, 3254–3267.
Chen, C., Jiang, L., Zhang, M., Pan, X., Peng, C., Huang, W., & Jiang, Q. (2019). Isodunnianol alleviates doxorubicin-induced myocardial injury by activating protective autophagy. Food & Function, 10, 2651–2657.
Yang, F., Teves, S. S., Kemp, C. J., & Henikoff, S. (2014). Doxorubicin, DNA torsion, and chromatin dynamics. Biochimica et Biophysica Acta, 1845, 84–89.
Jiang, X., Du, Y., Meng, X., Zhang, H., Zhao, D., Zhao, L., Chen, J., Xiao, S., & Jiang, H. (2018). Low-dose radiation enhanced inhibition of breast tumor Xenograft and reduced myocardial injury induced by doxorubicin. Dose Response, 16, 1559325818813061.
Damodar, G., Smitha, T., Gopinath, S., Vijayakumar, S., & Rao, Y. (2014). An evaluation of hepatotoxicity in breast cancer patients receiving injection doxorubicin. Annals of Medical and Health Sciences Research, 4, 74–79.
Wu, Y., Wang, J., Yu, X., Li, D., Han, X., & Fan, L. (2017). Sevoflurane ameliorates doxorubicin-induced myocardial injury by affecting the phosphorylation states of proteins in PI3K/Akt/mTOR signaling pathway. Cardiology Journal, 24, 409–418.
Qipshidze Kelm, N., Piell, K. M., Wang, E., & Cole, M. P. (2018). MicroRNAs as predictive biomarkers for myocardial injury in aged mice following myocardial infarction. Journal of Cellular Physiology, 233, 5214–5221.
Gong, Y. Y., Luo, J. Y., Wang, L., & Huang, Y. (2018). MicroRNAs regulating reactive oxygen species in cardiovascular diseases. Antioxidants & Redox Signaling, 29, 1092–1107.
Xiao, Y., Yan, W., Lu, L., Wang, Y., Lu, W., Cao, Y., & Cai, W. (2015). p38/p53/miR-200a-3p feedback loop promotes oxidative stress-mediated liver cell death. Cell Cycle, 14, 1548–1558.
Sun, X., Zuo, H., Liu, C., & Yang, Y. (2016). Overexpression of miR-200a protects cardiomyocytes against hypoxia-induced apoptosis by modulating the kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 signaling axis. International Journal of Molecular Medicine, 38, 1303–1311.
Hu, X., Liu, H., Wang, Z., Hu, Z., & Li, L. (2019). miR-200a attenuated doxorubicin-induced Cardiotoxicity through Upregulation of Nrf2 in mice. Oxidative Medicine and Cellular Longevity, 2019, 1512326.
Correra, R. M., Ollitrault, D., Valente, M., Mazzola, A., Adalsteinsson, B. T., Ferguson-Smith, A. C., Marazzi, G., & Sassoon, D. A. (2018). The imprinted gene Pw1/Peg3 regulates skeletal muscle growth, satellite cell metabolic state, and self-renewal. Scientific Reports, 8, 14649.
Ye, A., Kim, H., & Kim, J. (2017). PEG3 control on the mammalian MSL complex. PLoS One, 12, e0178363.
Yaniz-Galende, E., Roux, M., Nadaud, S., Mougenot, N., Bouvet, M., Claude, O., Lebreton, G., Blanc, C., Pinet, F., Atassi, F., Perret, C., Dierick, F., Dussaud, S., Leprince, P., Tregouet, D. A., Marazzi, G., Sassoon, D., & Hulot, J. S. (2017). Fibrogenic potential of PW1/Peg3 expressing cardiac stem cells. Journal of the American College of Cardiology, 70, 728–741.
Cui, L., Zhang, Y., Ge, X., Liu, J., Zhang, X., Li, H., & Li, Z. (2020). Downregulated PEG3 ameliorates cardiac fibrosis and myocardial injury in mice with ischemia/reperfusion through the NF-kappaB signaling pathway. Journal of Bioenergetics and Biomembranes, 52, 143–154.
Cappetta, D., Esposito, G., Piegari, E., Russo, R., Ciuffreda, L. P., Rivellino, A., Berrino, L., Rossi, F., De Angelis, A., & Urbanek, K. (2016). SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy. International Journal of Cardiology, 205, 99–110.
Ruan, Y., Dong, C., Patel, J., Duan, C., Wang, X., Wu, X., Cao, Y., Pu, L., Lu, D., Shen, T., & Li, J. (2015). SIRT1 suppresses doxorubicin-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways. Cellular Physiology and Biochemistry, 35, 1116–1124.
Raish, M. (2017). Momordica charantia polysaccharides ameliorate oxidative stress, hyperlipidemia, inflammation, and apoptosis during myocardial infarction by inhibiting the NF-kappaB signaling pathway. International Journal of Biological Macromolecules, 97, 544–551.
Guo, L., Li, S., Zhao, Y., Qian, P., Ji, F., Qian, L., Wu, X., & Qian, G. (2015). Silencing angiopoietin-like protein 4 (ANGPTL4) protects against lipopolysaccharide-induced acute lung injury via regulating SIRT1 /NF-kB pathway. Journal of Cellular Physiology, 230, 2390–2402.
Li, L., Wang, Q., Yuan, Z., Chen, A., Liu, Z., Li, H., & Wang, Z. (2018). Long non-coding RNA H19 contributes to hypoxia-induced CPC injury by suppressing Sirt1 through miR-200a-3p. Acta Biochimica et Biophysica Sinica (Shanghai), 50, 950–959.
Ma, L., & Li, Y. (2015). SIRT1: role in cardiovascular biology. Clinica Chimica Acta, 440, 8–15.
Yang, Y., Duan, W., Lin, Y., Yi, W., Liang, Z., Yan, J., Wang, N., Deng, C., Zhang, S., Li, Y., Chen, W., Yu, S., Yi, D., & Jin, Z. (2013). SIRT1 activation by curcumin pretreatment attenuates mitochondrial oxidative damage induced by myocardial ischemia reperfusion injury. Free Radical Biology & Medicine, 65, 667–679.
Frantz, S., Tillmanns, J., Kuhlencordt, P. J., Schmidt, I., Adamek, A., Dienesch, C., Thum, T., Gerondakis, S., Ertl, G., & Bauersachs, J. (2007). Tissue-specific effects of the nuclear factor kappaB subunit p50 on myocardial ischemia-reperfusion injury. The American Journal of Pathology, 171, 507–512.
Zhou, B., Yang, Y., & Li, C. (2019). SIRT1 inhibits hepatocellular carcinoma metastasis by promoting M1 macrophage polarization via NF-kappaB pathway. Oncotargets and Therapy, 12, 2519–2529.
Kyrychenko, S., Kyrychenko, V., Badr, M. A., Ikeda, Y., Sadoshima, J., & Shirokova, N. (2015). Pivotal role of miR-448 in the development of ROS-induced cardiomyopathy. Cardiovascular Research, 108, 324–334.
Wang, X., Jiang, F., Song, H., Li, X., Xian, J., & Gu, X. (2016). MicroRNA-200a-3p suppresses tumor proliferation and induces apoptosis by targeting SPAG9 in renal cell carcinoma. Biochemical and Biophysical Research Communications, 470, 620–626.
Hu, J., Zhang, L., Mei, Z., Jiang, Y., Yi, Y., Liu, L., Meng, Y., Zhou, L., Zeng, J., Wu, H., & Jiang, X. (2018). Interaction of E3 ubiquitin ligase MARCH7 with long noncoding RNA MALAT1 and autophagy-related protein ATG7 promotes autophagy and invasion in ovarian Cancer. Cellular Physiology and Biochemistry, 47, 654–666.
Yu, S., Yu, M., He, X., Wen, L., Bu, Z., & Feng, J. (2019). KCNQ1OT1 promotes autophagy by regulating miR-200a/FOXO3/ATG7 pathway in cerebral ischemic stroke. Aging Cell, 18, e12940.
Zhao, X. J., Yu, H. W., Yang, Y. Z., Wu, W. Y., Chen, T. Y., Jia, K. K., Kang, L. L., Jiao, R. Q., & Kong, L. D. (2018). Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway. Redox Biology, 18, 124–137.
Sun, R., & Zhang, L. (2019). Long non-coding RNA MALAT1 regulates cardiomyocytes apoptosis after hypoxia/reperfusion injury via modulating miR-200a-3p/PDCD4 axis. Biomedicine & Pharmacotherapy, 111, 1036–1045.
Nye, M. D., Hoyo, C., Huang, Z., Vidal, A. C., Wang, F., Overcash, F., Smith, J. S., Vasquez, B., Hernandez, B., Swai, B., Oneko, O., Mlay, P., Obure, J., Gammon, M. D., Bartlett, J. A., & Murphy, S. K. (2013). Associations between methylation of paternally expressed gene 3 (PEG3), cervical intraepithelial neoplasia and invasive cervical cancer. PLoS One, 8, e56325.
Neill, T., Sharpe, C., Owens, R. T., & Iozzo, R. V. (2017). Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy. The Journal of Biological Chemistry, 292, 16211–16220.
Theka, I., Sottile, F., Aulicino, F., Garcia, A. C., & Cosma, M. P. (2017). Reduced expression of paternally expressed Gene-3 enhances somatic cell reprogramming through mitochondrial activity perturbation. Scientific Reports, 7, 9705.
Nakazawa, H., Chang, K., Shinozaki, S., Yasukawa, T., Ishimaru, K., Yasuhara, S., Yu, Y. M., Martyn, J. A., Tompkins, R. G., Shimokado, K., & Kaneki, M. (2017). iNOS as a driver of inflammation and apoptosis in mouse skeletal muscle after burn injury: Possible involvement of Sirt1 S-Nitrosylation-mediated acetylation of p65 NF-kappaB and p53. PLoS One, 12, e0170391.
Quan, Y., Gong, L., He, J., Zhou, Y., Liu, M., Cao, Z., Li, Y., & Peng, C. (2019). Aloe emodin induces hepatotoxicity by activating NF-kappaB inflammatory pathway and P53 apoptosis pathway in zebrafish. Toxicology Letters, 306, 66–79.
Li, D., Wang, X., Huang, Q., Li, S., Zhou, Y., & Li, Z. (2018). Cardioprotection of CAPE-oNO2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-kappaB pathway in vivo and in vitro. Redox Biology, 15, 62–73.
Cui, L., Guo, J., Zhang, Q., Yin, J., Li, J., Zhou, W., Zhang, T., Yuan, H., Zhao, J., Zhang, L., Carmichael, P. L., & Peng, S. (2017). Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. Toxicology Letters, 275, 28–38.
Guo, R., Liu, W., Liu, B., Zhang, B., Li, W., & Xu, Y. (2015). SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: An insight into endoplasmic reticulum stress response mechanism. International Journal of Cardiology, 191, 36–45.
Jiang, W., Zhang, X., Hao, J., Shen, J., Fang, J., Dong, W., Wang, D., Zhang, X., Shui, W., Luo, Y., Lin, L., Qiu, Q., Liu, B., & Hu, Z. (2014). SIRT1 protects against apoptosis by promoting autophagy in degenerative human disc nucleus pulposus cells. Scientific Reports, 4, 7456.
Nopparat, C., Sinjanakhom, P., & Govitrapong, P. (2017). Melatonin reverses H2 O2 -induced senescence in SH-SY5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-kappaB. Journal of Pineal Research, 63.
Yan, S., Wang, M., Zhao, J., Zhang, H., Zhou, C., Jin, L., Zhang, Y., Qiu, X., Ma, B., & Fan, Q. (2016). MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis. International Journal of Molecular Medicine, 38, 201–209.
Acknowledgements
Thanks for all the contributors and participants.
Funding
This research was funded by the grants from the National Youth Natural Science Foundation of China (No. 81800056) and Key Research and Development Program of Hunan Province (No. 2019SK2021).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors report no relationships that could be construed as a conflict of interest.
Additional information
Handlind Editor: Y. Robert Li
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Fu, Q., Pan, H., Tang, Y. et al. MiR-200a-3p Aggravates DOX-Induced Cardiotoxicity by Targeting PEG3 Through SIRT1/NF-κB Signal Pathway. Cardiovasc Toxicol 21, 302–313 (2021). https://doi.org/10.1007/s12012-020-09620-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12012-020-09620-3