收缩性
心力衰竭
下调和上调
心功能曲线
压力过载
医学
背景(考古学)
调节器
内科学
小RNA
心脏病学
内分泌学
生物
心肌肥大
基因
古生物学
生物化学
作者
Zhiyong Lei,Christine Wahlquist,Hamid el Azzouzi,Janine C. Deddens,Diederik W.D. Kuster,Alain van Mil,Agustin Rojas‐Muñoz,Manon M. H. Huibers,Mark Mercola,Roel de Weger,Jolanda van der Velden,Junjie Xiao,Pieter A. Doevendans,Joost P. G. Sluijter
标识
DOI:10.3389/fcvm.2021.592362
摘要
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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