MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes.

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.

journal_name

Circ Res

journal_title

Circulation research

authors

Porrello ER,Johnson BA,Aurora AB,Simpson E,Nam YJ,Matkovich SJ,Dorn GW 2nd,van Rooij E,Olson EN

doi

10.1161/CIRCRESAHA.111.248880

subject

Has Abstract

pub_date

2011-09-02 00:00:00

pages

670-9

issue

6

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.111.248880

journal_volume

109

pub_type

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