Mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts

Jinghai Chen, Zhan Peng Huang, Hee Young Seok, Jian Ding, Masaharu Kataoka, Zheng Zhang, Xiaoyun Hu, Gang Wang, Zhiqiang Lin, Si Wang, Willam T. Pu, Ronglih Liao, Da Zhi Wang

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

RATIONALE:: Cardiomyocytes in adult mammalian hearts are terminally differentiated cells that have exited from the cell cycle and lost most of their proliferative capacity. Death of mature cardiomyocytes in pathological cardiac conditions and the lack of regeneration capacity of adult hearts are primary causes of heart failure and mortality. However, how cardiomyocyte proliferation in postnatal and adult hearts becomes suppressed remains largely unknown. The miR-17-92 cluster was initially identified as a human oncogene that promotes cell proliferation. However, its role in the heart remains unknown. OBJECTIVE:: To test the hypothesis that miR-17-92 participates in the regulation of cardiomyocyte proliferation in postnatal and adult hearts. METHODS AND RESULTS:: We deleted miR-17-92 cluster from embryonic and postnatal mouse hearts and demonstrated that miR-17-92 is required for cardiomyocyte proliferation in the heart. Transgenic overexpression of miR-17-92 in cardiomyocytes is sufficient to induce cardiomyocyte proliferation in embryonic, postnatal, and adult hearts. Moreover, overexpression of miR-17-92 in adult cardiomyocytes protects the heart from myocardial infarction-induced injury. Similarly, we found that members of miR-17-92 cluster, miR-19 in particular, are required for and sufficient to induce cardiomyocyte proliferation in vitro. We identified phosphatase and tensin homolog, a tumor suppressor, as an miR-17-92 target to mediate the function of miR-17-92 in cardiomyocyte proliferation. CONCLUSIONS:: Our studies therefore identify miR-17-92 as a critical regulator of cardiomyocyte proliferation, and suggest this cluster of microRNAs could become therapeutic targets for cardiac repair and heart regeneration.

Original languageEnglish
Pages (from-to)1557-1566
Number of pages10
JournalCirculation research
Volume112
Issue number12
DOIs
Publication statusPublished - 2013 Jun 7
Externally publishedYes

Keywords

  • PTEN
  • cardiomyocyte proliferation
  • cell cycle
  • heart disease
  • miR-17-92
  • myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Chen, J., Huang, Z. P., Seok, H. Y., Ding, J., Kataoka, M., Zhang, Z., Hu, X., Wang, G., Lin, Z., Wang, S., Pu, W. T., Liao, R., & Wang, D. Z. (2013). Mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. Circulation research, 112(12), 1557-1566. https://doi.org/10.1161/CIRCRESAHA.112.300658