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. 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.592362

DOI=10.3389/fcvm.2021.592362

ISSN=2297-055X

ABSTRACT=Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased con-tractile 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 mo-lecular 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 identified 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 thera-peutic approach to promote cardiac function in heart failure patients.