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Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart

Heart failure is characterized by a debilitating decline in cardiac function(1), and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy(2,3). microRNAs (miRs) are dysregulated with hea...

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Autores principales: Wahlquist, Christine, Jeong, Dongtak, Rojas-Muñoz, Agustin, Kho, Changwon, Lee, Ahyoung, Mitsuyama, Shinichi, van Mil, Alain, Jin Park, Woo, Sluijter, Joost P. G., Doevendans, Pieter A. F., Hajjar, Roger J., Mercola, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131725/
https://www.ncbi.nlm.nih.gov/pubmed/24670661
http://dx.doi.org/10.1038/nature13073
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author Wahlquist, Christine
Jeong, Dongtak
Rojas-Muñoz, Agustin
Kho, Changwon
Lee, Ahyoung
Mitsuyama, Shinichi
van Mil, Alain
Jin Park, Woo
Sluijter, Joost P. G.
Doevendans, Pieter A. F.
Hajjar, Roger J.
Mercola, Mark
author_facet Wahlquist, Christine
Jeong, Dongtak
Rojas-Muñoz, Agustin
Kho, Changwon
Lee, Ahyoung
Mitsuyama, Shinichi
van Mil, Alain
Jin Park, Woo
Sluijter, Joost P. G.
Doevendans, Pieter A. F.
Hajjar, Roger J.
Mercola, Mark
author_sort Wahlquist, Christine
collection PubMed
description Heart failure is characterized by a debilitating decline in cardiac function(1), and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy(2,3). microRNAs (miRs) are dysregulated with heart failure(4,5) but whether they control contractility or constitute therapeutic targets remain speculative. Using high throughput, functional screening of the human microRNAome, we identified miRs that suppress intracellular calcium handling in heart muscle by interacting with mRNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a. Of 875 miRs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas AAV9-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 dramatically halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggests that it might be targeted therapeutically to restore function.
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spelling pubmed-41317252014-10-24 Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart Wahlquist, Christine Jeong, Dongtak Rojas-Muñoz, Agustin Kho, Changwon Lee, Ahyoung Mitsuyama, Shinichi van Mil, Alain Jin Park, Woo Sluijter, Joost P. G. Doevendans, Pieter A. F. Hajjar, Roger J. Mercola, Mark Nature Article Heart failure is characterized by a debilitating decline in cardiac function(1), and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy(2,3). microRNAs (miRs) are dysregulated with heart failure(4,5) but whether they control contractility or constitute therapeutic targets remain speculative. Using high throughput, functional screening of the human microRNAome, we identified miRs that suppress intracellular calcium handling in heart muscle by interacting with mRNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a. Of 875 miRs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas AAV9-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 dramatically halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggests that it might be targeted therapeutically to restore function. 2014-03-12 2014-04-24 /pmc/articles/PMC4131725/ /pubmed/24670661 http://dx.doi.org/10.1038/nature13073 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wahlquist, Christine
Jeong, Dongtak
Rojas-Muñoz, Agustin
Kho, Changwon
Lee, Ahyoung
Mitsuyama, Shinichi
van Mil, Alain
Jin Park, Woo
Sluijter, Joost P. G.
Doevendans, Pieter A. F.
Hajjar, Roger J.
Mercola, Mark
Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart
title Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart
title_full Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart
title_fullStr Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart
title_full_unstemmed Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart
title_short Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart
title_sort inhibition of mir-25 improves cardiac contractility in the failing heart
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131725/
https://www.ncbi.nlm.nih.gov/pubmed/24670661
http://dx.doi.org/10.1038/nature13073
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