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Nature. 2019 May;569(7756):418-422. doi: 10.1038/s41586-019-1191-6. Epub 2019 May 8.

MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs.

Author information

1
Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
2
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
3
Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
4
School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre, London, UK.
5
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
6
Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
7
Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy. fabio.recchia@santannapisa.it.
8
Fondazione Toscana Gabriele Monasterio, Pisa, Italy. fabio.recchia@santannapisa.it.
9
Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. fabio.recchia@santannapisa.it.
10
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy. mauro.giacca@kcl.ac.uk.
11
School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre, London, UK. mauro.giacca@kcl.ac.uk.
12
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy. mauro.giacca@kcl.ac.uk.

Abstract

Prompt coronary catheterization and revascularization have markedly improved the outcomes of myocardial infarction, but have also resulted in a growing number of surviving patients with permanent structural damage of the heart, which frequently leads to heart failure. There is an unmet clinical need for treatments for this condition1, particularly given the inability of cardiomyocytes to replicate and thereby regenerate the lost contractile tissue2. Here we show that expression of human microRNA-199a in infarcted pig hearts can stimulate cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. However, subsequent persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however dosage of this therapy needs to be tightly controlled.

PMID:
31068698
DOI:
10.1038/s41586-019-1191-6

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