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miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a

Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased contractile capacity due to dysregulated calcium handling. Unfortunately, the underlying mechanism causing impaired calcium handling is still not fully understood. Previously the miR-132/212 family was identi...

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Autores principales: Lei, Zhiyong, Wahlquist, Christine, el Azzouzi, Hamid, Deddens, Janine C., Kuster, Diederik, van Mil, Alain, Rojas-Munoz, Agustin, Huibers, Manon M., Mercola, Mark, de Weger, Roel, Van der Velden, Jolanda, Xiao, Junjie, Doevendans, Pieter A., Sluijter, Joost P. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017124/
https://www.ncbi.nlm.nih.gov/pubmed/33816571
http://dx.doi.org/10.3389/fcvm.2021.592362
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author Lei, Zhiyong
Wahlquist, Christine
el Azzouzi, Hamid
Deddens, Janine C.
Kuster, Diederik
van Mil, Alain
Rojas-Munoz, Agustin
Huibers, Manon M.
Mercola, Mark
de Weger, Roel
Van der Velden, Jolanda
Xiao, Junjie
Doevendans, Pieter A.
Sluijter, Joost P. G.
author_facet Lei, Zhiyong
Wahlquist, Christine
el Azzouzi, Hamid
Deddens, Janine C.
Kuster, Diederik
van Mil, Alain
Rojas-Munoz, Agustin
Huibers, Manon M.
Mercola, Mark
de Weger, Roel
Van der Velden, Jolanda
Xiao, Junjie
Doevendans, Pieter A.
Sluijter, Joost P. G.
author_sort Lei, Zhiyong
collection PubMed
description Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased contractile capacity due to dysregulated calcium handling. Unfortunately, the underlying mechanism causing impaired calcium handling is still not fully understood. Previously the miR-132/212 family was identified as a regulator of cardiac function in the failing mouse heart, and pharmaceutically inhibition of miR-132 is beneficial for heart failure. In this study, we further investigated the molecular mechanisms of miR-132/212 in modulating cardiomyocyte contractility in the context of the pathological progression of heart failure. We found that upregulated miR-132/212 expressions in all examined hypertrophic heart failure mice models. The overexpression of miR-132/212 prolongs calcium decay in isolated neonatal rat cardiomyocytes, whereas cardiomyocytes isolated from miR-132/212 KO mice display enhanced contractility in comparison to wild type controls. In response to chronic pressure-overload, miR-132/212 KO mice exhibited a blunted deterioration of cardiac function. Using a combination of biochemical approaches and in vitro assays, we confirmed that miR-132/212 regulates SERCA2a by targeting the 3′-end untranslated region of SERCA2a. Additionally, we also confirmed PTEN as a direct target of miR-132/212 and potentially participates in the cardiac response to miR132/212. In end-stage heart failure patients, miR-132/212 is upregulated and correlates with reduced SERCA2a expression. The up-regulation of miR-132/212 in heart failure impairs cardiac contractile function by targeting SERCA2a, suggesting that pharmaceutical inhibition of miR-132/212 might be a promising therapeutic approach to promote cardiac function in heart failure patients.
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spelling pubmed-80171242021-04-03 miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a Lei, Zhiyong Wahlquist, Christine el Azzouzi, Hamid Deddens, Janine C. Kuster, Diederik van Mil, Alain Rojas-Munoz, Agustin Huibers, Manon M. Mercola, Mark de Weger, Roel Van der Velden, Jolanda Xiao, Junjie Doevendans, Pieter A. Sluijter, Joost P. G. Front Cardiovasc Med Cardiovascular Medicine Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased contractile capacity due to dysregulated calcium handling. Unfortunately, the underlying mechanism causing impaired calcium handling is still not fully understood. Previously the miR-132/212 family was identified as a regulator of cardiac function in the failing mouse heart, and pharmaceutically inhibition of miR-132 is beneficial for heart failure. In this study, we further investigated the molecular mechanisms of miR-132/212 in modulating cardiomyocyte contractility in the context of the pathological progression of heart failure. We found that upregulated miR-132/212 expressions in all examined hypertrophic heart failure mice models. The overexpression of miR-132/212 prolongs calcium decay in isolated neonatal rat cardiomyocytes, whereas cardiomyocytes isolated from miR-132/212 KO mice display enhanced contractility in comparison to wild type controls. In response to chronic pressure-overload, miR-132/212 KO mice exhibited a blunted deterioration of cardiac function. Using a combination of biochemical approaches and in vitro assays, we confirmed that miR-132/212 regulates SERCA2a by targeting the 3′-end untranslated region of SERCA2a. Additionally, we also confirmed PTEN as a direct target of miR-132/212 and potentially participates in the cardiac response to miR132/212. In end-stage heart failure patients, miR-132/212 is upregulated and correlates with reduced SERCA2a expression. The up-regulation of miR-132/212 in heart failure impairs cardiac contractile function by targeting SERCA2a, suggesting that pharmaceutical inhibition of miR-132/212 might be a promising therapeutic approach to promote cardiac function in heart failure patients. Frontiers Media S.A. 2021-03-19 /pmc/articles/PMC8017124/ /pubmed/33816571 http://dx.doi.org/10.3389/fcvm.2021.592362 Text en Copyright © 2021 Lei, Wahlquist, el Azzouzi, Deddens, Kuster, van Mil, Rojas-Munoz, Huibers, Mercola, de Weger, Van der Velden, Xiao, Doevendans and Sluijter. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Lei, Zhiyong
Wahlquist, Christine
el Azzouzi, Hamid
Deddens, Janine C.
Kuster, Diederik
van Mil, Alain
Rojas-Munoz, Agustin
Huibers, Manon M.
Mercola, Mark
de Weger, Roel
Van der Velden, Jolanda
Xiao, Junjie
Doevendans, Pieter A.
Sluijter, Joost P. G.
miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a
title miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a
title_full miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a
title_fullStr miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a
title_full_unstemmed miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a
title_short miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a
title_sort mir-132/212 impairs cardiomyocytes contractility in the failing heart by suppressing serca2a
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017124/
https://www.ncbi.nlm.nih.gov/pubmed/33816571
http://dx.doi.org/10.3389/fcvm.2021.592362
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