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Cardiovasc Res. 2016 May 1;110(1):73-84. doi: 10.1093/cvr/cvw031. Epub 2016 Feb 7.

Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways.

Author information

1
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne 1011, Switzerland.
2
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
3
Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
4
Institute for Research in Ophthalmology, Sion, Switzerland.
5
Lausanne Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland.
6
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
7
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne 1011, Switzerland thierry.pedrazzini@chuv.ch.

Abstract

AIMS:

The adult mammalian heart has poor regenerative capacity. In contrast, the zebrafish heart retains a robust capacity for regeneration into adulthood. These distinct responses are consequences of a differential utilization of evolutionary-conserved gene regulatory networks in the damaged heart. To systematically identify miRNA-dependent networks controlling cardiac repair following injury, we performed comparative gene and miRNA profiling of the cardiac transcriptome in adult mice and zebrafish.

METHODS AND RESULTS:

Using an integrated approach, we show that 45 miRNA-dependent networks, involved in critical biological pathways, are differentially modulated in the injured zebrafish vs. mouse hearts. We study, more particularly, the miR-26a-dependent response. Therefore, miR-26a is down-regulated in the fish heart after injury, whereas its expression remains constant in the mouse heart. Targets of miR-26a involve activators of the cell cycle and Ezh2, a component of the polycomb repressive complex 2 (PRC2). Importantly, PRC2 exerts repressive functions on negative regulators of the cell cycle. In cultured neonatal cardiomyocytes, inhibition of miR-26a stimulates, therefore, cardiomyocyte proliferation. Accordingly, miR-26a knockdown prolongs the proliferative window of cardiomyocytes in the post-natal mouse heart.

CONCLUSIONS:

This novel strategy identifies a series of miRNAs and associated pathways, in particular miR-26a, which represent attractive therapeutic targets for inducing repair in the injured heart.

KEYWORDS:

Mouse; Myocardial infarction; Repair mechanisms; Zebrafish; miRNAs

PMID:
26857418
PMCID:
PMC4798047
DOI:
10.1093/cvr/cvw031
[Indexed for MEDLINE]
Free PMC Article

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