miR-15 Family Regulates Postnatal Mitotic Arrest of Cardiomyocytes

Abstract

Rationale Mammalian cardiomyocytes withdraw from the cell cycle during early post-natal development, which significantly limits the capacity of the adult mammalian heart to regenerate following injury. The regulatory mechanisms which 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 up- or down-regulated 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 up-regulated miRNA during this period, with expression levels almost 6-fold higher in P10 ventricles relative to P1. Precocious over-expression of miR-195 in the embryonic heart was associated with ventricular hypoplasia and ventricular septal defects in βMHC-miR-195 transgenic mice. Using global gene profiling and Argonaute-2 immunoprecipitation approaches, we show that miR-195 regulates the expression of a number of cell cycle genes, including checkpoint kinase 1 (Chek1), which we identify as a highly conserved direct target of miR-195. Finally, we demonstrate that knock-down of the miR-15 family in neonatal mice using locked nucleic acid (LNA)-modified antimiRs is associated with an increased number of mitotic cardiomyocytes and de-repression of Chek1. Conclusions These findings suggest that up-regulation of the miR-15 family during the neonatal period may be an important regulatory mechanism governing cardiomyocyte cell cycle withdrawal and binucleation.

Blockade of senescence‐associated micro RNA ‐195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells.

“…Results of this study showed that the expression of miR‐195 was increased in older SkMs but decreased during the induction of de novo reprogramming of old SkMs into iPSCs. Although previous studies have demonstrated that miR‐195 is associated with cardiac hypertrophy and heart failure by controlling cell cycle‐related genes that affect aging (Porrello et al ., 2011), we hypothesized that upregulated miR‐195 is a senescence‐associated miR in reprogramming. Intriguingly, there was an observed discrepancy between miR‐195 and SA‐β‐gal expression in early passaged old SkMs in this study.…”

MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis

“…The most shared miRNAs are endothelial cell (EC) derived and include miR‐126/17–92/15/34 clusters as representing highly circulating miRNAs 2, 3, 4, 5, 6.…”

“…The miR‐15 and ‐34 families exert tumour suppressor activity in multiple adult tissues 4, 5, 28, 33. In clinical studies on patients with CVD, the anti‐atherosclerotic and vasodilatation effects of statins have been addressed to induce the bioactivity of NOS and Bcl‐2 in endothelium.…”

“…The apoptosis effect of the miR‐15 family has been addressed to down‐regulate SIRT1, cell cycle regulators and Bcl‐2 5, 32.…”

“…The major targets of the miR‐15 family are predicted to be regulators of cell cycle in mitotosis, chromosome condensation and cellular response to DNA damage 5, 32, 41.…”