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E3 Ubiquitin Ligase ASB14 Inhibits Cardiomyocyte Proliferation by Regulating MAPRE2 Ubiquitination

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Abstract

The ubiquitin proteasome system is a highly specific and selective protein regulatory system that plays an essential role in the regulation of the cell cycle. Despite its significance, the role of ubiquitination in cardiomyocyte proliferation remains largely unclear. This study aimed to investigate the potential impact of E3 ubiquitin ligase ASB14 (Ankyrin Repeat And SOCS Box Containing 14) on cardiac regeneration. We conducted a microarray analysis of apical resection ventricle tissues, and our findings revealed that ASB14 was down-regulated during the cardiac regenerative response. Subsequently, we examined the effect of ASB14 silencing on cardiomyocyte nuclear proliferation both in vitro and in vivo. Our results indicated that ASB14 silencing promoted cardiomyocyte nuclear proliferation, suggesting that ASB14 may play a role in regulating cardiac regeneration. To further investigate the potential therapeutic implications of ASB14 deficiency, we examined the cardiac function of mice with ASB14 deficiency in response to ischemic injury. Our findings showed that mice with ASB14 deficiency exhibited preserved cardiac function and a therapeutic effect in response to ischemic injury, which was attributed to the enhancement of cardiomyocyte nuclear proliferation. To elucidate the underlying mechanisms, we investigated the effect of ASB14 on microtubule-associated protein RP/EB family member 2 (MAPRE2) protein degradation. Our results indicated that the loss of ASB14 decreased the degradation of MAPRE2 protein, subsequently promoting cardiomyocyte nuclear proliferation and enhancing cardiac repair after myocardial infarction (MI). In conclusion, our study provides evidence that inhibition of ASB14-mediated MAPRE2 ubiquitination promotes cardiomyocyte nuclear proliferation, which may serve as a potential target for treating heart failure induced by MI injury.

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Data availability

The microarray data was downloaded from Gene Expression Omnibus (accession number, GSE154071). No datasets were generated or analysed during the current study.

References

  1. Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Delling, F. N., Djousse, L., Elkind, M. S. V., Ferguson, J. F., Fornage, M., Khan, S. S., Kissela, B. M., Knutson, K. L., Kwan, T. W., Lackland, D. T., Lewis, T. T., Lichtman, J. H., Longenecker, C. T., Loop, M. S., Lutsey, P. L., Martin, S. S., Matsushita, K., Moran, A. E., Mussolino, M. E., Perak, A. M., Rosamond, W. D., Roth, G. A., Sampson, U. K. A., Satou, G. M., Schroeder, E. B., Shah, S. H., Shay, C. M., Spartano, N. L., Stokes, A., Tirschwell, D. L., VanWagner, L. B. & & Tsao, C. W. (2020). Heart disease and stroke statistics update: a report from the American heart association.Circulation, 141, e139–e596. https://doi.org/10.1161/cir.0000000000000757.

    Article  PubMed  Google Scholar 

  2. Ongstad, E. L., & Gourdie, R. G. (2016). Can heart function lost to disease be regenerated by therapeutic targeting of cardiac scar tissue? Seminar in Cellular and Developmental Biology, 58, 41–54. https://doi.org/10.1016/j.semcdb.2016.05.020.

    Article  Google Scholar 

  3. Senyo, S. E., Steinhauser, M. L., Pizzimenti, C. L., Yang, V. K., Cai, L., Wang, M., Wu, T. D., Guerquin-Kern, J. L., Lechene, C. P., & Lee, R. T. (2013). Mammalian heart renewal by pre-existing cardiomyocytes. Nature, 493, 433–436. https://doi.org/10.1038/nature11682.

    Article  CAS  PubMed  ADS  Google Scholar 

  4. Porrello, E. R., Mahmoud, A. I., Simpson, E., Hill, J. A., Richardson, J. A., Olson, E. N., & Sadek, H. A. (2011). Transient regenerative potential of the neonatal mouse heart. Science, 331, 1078–1080. https://doi.org/10.1126/science.1200708.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  5. Yu, W., Huang, X., Tian, X., Zhang, H., He, L., Wang, Y., Nie, Y., Hu, S., Lin, Z., Zhou, B., Pu, W., Lui, K. O., & Zhou, B. (2016). GATA4 regulates Fgf16 to promote heart repair after injury. Development, 143, 936–949. https://doi.org/10.1242/dev.130971.

    Article  CAS  PubMed  Google Scholar 

  6. Fu, W., Ren, H., Shou, J., Liao, Q., Li, L., Shi, Y., Jose, P. A., Zeng, C., & Wang, W. E. (2022). Loss of NPPA-AS1 promotes heart regeneration by stabilizing SFPQ-NONO heteromer-induced DNA repair. Basic Research in Cardiology, 117, 10 https://doi.org/10.1007/s00395-022-00921-y.

    Article  CAS  PubMed  Google Scholar 

  7. Fan, Y., Cheng, Y., Li, Y., Chen, B., Wang, Z., Wei, T., Zhang, H., Guo, Y., Wang, Q., Wei, Y., Chen, F., Sha, J., Guo, X., & Wang, L. (2020). Phosphoproteomic analysis of neonatal regenerative myocardium revealed important roles of checkpoint Kinase 1 via activating mammalian target of rapamycin C1/Ribosomal protein S6 Kinase b-1 pathway. Circulation, 141, 1554–1569. https://doi.org/10.1161/circulationaha.119.040747.

    Article  CAS  PubMed  Google Scholar 

  8. Willis, M. S., Townley-Tilson, W. H., Kang, E. Y., Homeister, J. W., & Patterson, C. (2010). Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circulation Research, 106, 463–478. https://doi.org/10.1161/circresaha.109.208801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang, C., Yang, H., & Gao, C. (2019). Potential biomarkers for heart failure. Journal in Cellular Physiology, 234, 9467–9474. https://doi.org/10.1002/jcp.27632.

    Article  CAS  Google Scholar 

  10. Li, L. T., Jiang, G., Chen, Q., & Zheng, J. N. (2015). Ki67 is a promising molecular target in the diagnosis of cancer (review). Molecular Medicine Reports, 11, 1566–1572. https://doi.org/10.3892/mmr.2014.2914.

    Article  CAS  PubMed  Google Scholar 

  11. Auchampach, J., Han, L., Huang, G. N., Kühn, B., Lough, J. W., O’Meara, C. C., Payumo, A. Y., Rosenthal, N. A., Sucov, H. M., Yutzey, K. E., & Patterson, M. (2022). Measuring cardiomyocyte cell-cycle activity and proliferation in the age of heart regeneration. American Journal in Physiological Heart Circulation Physiology, 322, H579–h596. https://doi.org/10.1152/ajpheart.00666.2021.

    Article  CAS  Google Scholar 

  12. Wang, X., Li, Y., He, M., Kong, X., Jiang, P., Liu, X., Diao, L., Zhang, X., Li, H., Ling, X., **a, S., Liu, Z., Liu, Y., Cui, C. P., Wang, Y., Tang, L., Zhang, L., He, F., & Li, D. (2022). UbiBrowser 2.0: a comprehensive resource for proteome-wide known and predicted ubiquitin ligase/deubiquitinase-substrate interactions in eukaryotic species. Nucleic Acids Research, 50, D719–d728. https://doi.org/10.1093/nar/gkab962.

    Article  CAS  PubMed  Google Scholar 

  13. Iimori, M., Watanabe, S., Kiyonari, S., Matsuoka, K., Sakasai, R., Saeki, H., Oki, E., Kitao, H., & Maehara, Y. (2016). Phosphorylation of EB2 by Aurora B and CDK1 ensures mitotic progression and genome stability. Nature Communications, 7, 11117 https://doi.org/10.1038/ncomms11117.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  14. Zhu, W., Zhang, E., Zhao, M., Chong, Z., Fan, C., Tang, Y., Hunter, J. D., Borovjagin, A. V., Walcott, G. P., Chen, J. Y., Qin, G., & Zhang, J. (2018). Regenerative potential of neonatal porcine hearts. Circulation, 138, 2809–2816. https://doi.org/10.1161/circulationaha.118.034886.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sun, X., Han, Q., Luo, H., Pan, X., Ji, Y., Yang, Y., Chen, H., Wang, F., Lai, W., Guan, X., Zhang, Q., Tang, Y., Chu, J., Yu, J., Shou, W., Deng, Y., & Li, X. (2017). Profiling analysis of long non-coding RNAs in early postnatal mouse hearts. Scientific Reports, 7, 43485 https://doi.org/10.1038/srep43485.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  16. Alkass, K., Panula, J., Westman, M., Wu, T. D., Guerquin-Kern, J. L., & Bergmann, O. (2015). No evidence for cardiomyocyte number expansion in preadolescent mice. Cell, 163, 1026–1036. https://doi.org/10.1016/j.cell.2015.10.035.

    Article  CAS  PubMed  Google Scholar 

  17. Hosseini, S. M., Okoye, I., Chaleshtari, M. G., Hazhirkarzar, B., Mohamadnejad, J., Azizi, G., Hojjat-Farsangi, M., Mohammadi, H., Shotorbani, S. S., & Jadidi-Niaragh, F. (2019). E2 ubiquitin-conjugating enzymes in cancer: implications for immunotherapeutic interventions. Clinica Chimica Acta, 498, 126–134. https://doi.org/10.1016/j.cca.2019.08.020.

    Article  CAS  Google Scholar 

  18. Tamamori-Adachi, M., Hayashida, K., Nobori, K., Omizu, C., Yamada, K., Sakamoto, N., Kamura, T., Fukuda, K., Ogawa, S., Nakayama, K. I., & Kitajima, S. (2004). Down-regulation of p27Kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4. evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation. The Journal of Biological Chemistry, 279, 50429–50436. https://doi.org/10.1074/jbc.M403084200.

    Article  CAS  PubMed  Google Scholar 

  19. Li, B., Li, M., Li, X., Li, H., Lai, Y., Huang, S., He, X., Si, X., Zheng, H., Liao, W., Liao, Y., & Bin, J. (2019). Sirt1-inducible deacetylation of p21 promotes cardiomyocyte proliferation. Aging (Albany NY), 11, 12546–12567. https://doi.org/10.18632/aging.102587.

    Article  CAS  PubMed  Google Scholar 

  20. Huang, S., Li, X., Zheng, H., Si, X., Li, B., Wei, G., Li, C., Chen, Y., Chen, Y., Liao, W., Liao, Y., & Bin, J. (2019). Loss of super-enhancer-regulated circRNA Nfix induces cardiac regeneration after myocardial infarction in adult mice. Circulation, 139, 2857–2876. https://doi.org/10.1161/circulationaha.118.038361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhong, F. J., Li, Y. M., Xu, C., Sun, B., Wang, J. L., & Yang, L. Y. (2021). EB2 promotes hepatocellular carcinoma proliferation and metastasis via MAPK/ERK pathway by modulating microtubule dynamics. Clinical Science (Lond), 135, 847–864. https://doi.org/10.1042/cs20201500.

    Article  CAS  Google Scholar 

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Funding

The Medical Project of Scientific and Technological Breakthroughs in Henan Province (No. SBGJ202303049).

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Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Yanpeng Yang & Chunguang Qiu

  2. Cardiac Care Unit, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China

    Dongpu Ma, Bo Liu & Feifei Lv

  3. Department of Integrated Chinese and Western Medicine, Henan Cancer Hospital and Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China

    Xu Sun

  4. Tuberculosis Department No. 1 Ward, Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, China

    Wei Fu

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  1. Yanpeng Yang
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  4. Xu Sun
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  5. Wei Fu
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Contributions

Y.Y. performed most of the experiments. D.M. performed most of the analyses, with support from B.L. and X.S. Y.Y, F.L and W.F. performed the experiments. Q.C. supervised the study. All authors reviewed the manuscript.

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Correspondence to Chunguang Qiu.

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The authors declare no competing interests.

Ethical approval

Animal care and experimental procedures in the present study were approved by the Institutional Animal Care and Use Committee of Zhengzhou University (ethical approval number: 202353) and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

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Yang, Y., Ma, D., Liu, B. et al. E3 Ubiquitin Ligase ASB14 Inhibits Cardiomyocyte Proliferation by Regulating MAPRE2 Ubiquitination. Cell Biochem Biophys (2024). https://doi.org/10.1007/s12013-024-01223-x

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