MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes

Enzo R. Porrello, Brett A. Johnson, Arin B. Aurora, Emma Simpson, Young Jae Nam, Scot J. Matkovich, Gerald W. Dorn, Eva Van Rooij, Eric N. Olson

Research output: Contribution to journalArticle

283 Scopus citations

Abstract

RATIONALE: Mammalian cardiomyocytes withdraw from the cell cycle during early postnatal development, which significantly limits the capacity of the adult mammalian heart to regenerate after injury. The regulatory mechanisms that govern cardiomyocyte cell cycle withdrawal and binucleation are poorly understood. OBJECTIVE: Given the potential of microRNAs (miRNAs) to influence large gene networks and modify complex developmental and disease phenotypes, we searched for miRNAs that were regulated during the postnatal switch to terminal differentiation. METHODS AND RESULTS: Microarray analysis revealed subsets of miRNAs that were upregulated or downregulated in cardiac ventricles from mice at 1 and 10 days of age (P1 and P10). Interestingly, miR-195 (a member of the miR-15 family) was the most highly upregulated miRNA during this period, with expression levels almost 6-fold higher in P10 ventricles relative to P1. Precocious overexpression of miR-195 in the embryonic heart was associated with ventricular hypoplasia and ventricular septal defects in β-myosin heavy chain-miR-195 transgenic mice. Using global gene profiling and argonaute-2 immunoprecipitation approaches, we showed that miR-195 regulates the expression of a number of cell cycle genes, including checkpoint kinase 1 (Chek1), which we identified as a highly conserved direct target of miR-195. Finally, we demonstrated that knockdown of the miR-15 family in neonatal mice with locked nucleic acid-modified anti-miRNAs was associated with an increased number of mitotic cardiomyocytes and derepression of Chek1. CONCLUSIONS: These findings suggest that upregulation of the miR-15 family during the neonatal period may be an important regulatory mechanism governing cardiomyocyte cell cycle withdrawal and binucleation.

Original languageEnglish (US)
Pages (from-to)670-679
Number of pages10
JournalCirculation research
Volume109
Issue number6
DOIs
StatePublished - Sep 2 2011

Keywords

  • binucleation
  • cell cycle
  • checkpoint kinase 1
  • miR-195
  • miRNA
  • neonate

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Porrello, E. R., Johnson, B. A., Aurora, A. B., Simpson, E., Nam, Y. J., Matkovich, S. J., Dorn, G. W., Van Rooij, E., & Olson, E. N. (2011). MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circulation research, 109(6), 670-679. https://doi.org/10.1161/CIRCRESAHA.111.248880