Back to Search Start Over

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

Authors :
Zhiyong Lei
Christine Wahlquist
Hamid el Azzouzi
Janine C. Deddens
Diederik Kuster
Alain van Mil
Agustin Rojas-Munoz
Manon M. Huibers
Mark Mercola
Roel de Weger
Jolanda Van der Velden
Junjie Xiao
Pieter A. Doevendans
Joost P. G. Sluijter
Source :
Frontiers in Cardiovascular Medicine, Vol 8 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

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.

Details

Language :
English
ISSN :
2297055X
Volume :
8
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cardiovascular Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.8911eb526d44c128a96bcd2108ada95
Document Type :
article
Full Text :
https://doi.org/10.3389/fcvm.2021.592362