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

189 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

Fingerprint

Cardiac Myocytes
Regeneration
MicroRNAs
Oncogenes
Phosphoric Monoester Hydrolases
Cell Cycle
Heart Failure
Myocardial Infarction
Cell Proliferation
Mortality
Wounds and Injuries

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. / Chen, Jinghai; Huang, Zhan Peng; Seok, Hee Young; Ding, Jian; Kataoka, Masaharu; Zhang, Zheng; Hu, Xiaoyun; Wang, Gang; Lin, Zhiqiang; Wang, Si; Pu, Willam T.; Liao, Ronglih; Wang, Da Zhi.

In: Circulation research, Vol. 112, No. 12, 07.06.2013, p. 1557-1566.

Research output: Contribution to journalArticle

Chen, J, Huang, ZP, Seok, HY, Ding, J, Kataoka, M, Zhang, Z, Hu, X, Wang, G, Lin, Z, Wang, S, Pu, WT, Liao, R & Wang, DZ 2013, 'Mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts', Circulation research, vol. 112, no. 12, pp. 1557-1566. https://doi.org/10.1161/CIRCRESAHA.112.300658
Chen, Jinghai ; Huang, Zhan Peng ; Seok, Hee Young ; Ding, Jian ; Kataoka, Masaharu ; Zhang, Zheng ; Hu, Xiaoyun ; Wang, Gang ; Lin, Zhiqiang ; Wang, Si ; Pu, Willam T. ; Liao, Ronglih ; Wang, Da Zhi. / Mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. In: Circulation research. 2013 ; Vol. 112, No. 12. pp. 1557-1566.
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AU - Chen, Jinghai

AU - Huang, Zhan Peng

AU - Seok, Hee Young

AU - Ding, Jian

AU - Kataoka, Masaharu

AU - Zhang, Zheng

AU - Hu, Xiaoyun

AU - Wang, Gang

AU - Lin, Zhiqiang

AU - Wang, Si

AU - Pu, Willam T.

AU - Liao, Ronglih

AU - Wang, Da Zhi

PY - 2013/6/7

Y1 - 2013/6/7

N2 - 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.

AB - 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.

KW - cardiomyocyte proliferation

KW - cell cycle

KW - heart disease

KW - miR-17-92

KW - myocardial infarction

KW - PTEN

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