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
Experimental Cardiology Laboratory, Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.
Division Lab, Central Diagnosis Laboratory Research, University Medical Center Utrecht, Utrecht, Netherlands.
Front Cardiovasc Med. 2021 Mar 19;8:592362. doi: 10.3389/fcvm.2021.592362. eCollection 2021.
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 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.
心脏功能受损是心力衰竭的一个标志，主要表现为由于钙处理失调导致的收缩能力下降。不幸的是，导致钙处理受损的潜在机制仍未完全清楚。先前已确定miR-132/212家族是衰竭小鼠心脏中心脏功能的调节因子，对miR-132的药物抑制对心力衰竭有益。在本研究中，我们进一步研究了miR-132/212在心力衰竭病理进展背景下调节心肌细胞收缩性的分子机制。我们发现，在所有检测的肥厚性心力衰竭小鼠模型中，miR-132/212表达上调。miR-132/212的过表达延长了分离的新生大鼠心肌细胞中的钙衰减，而与野生型对照相比，从miR-132/212基因敲除小鼠分离的心肌细胞表现出增强的收缩性。在慢性压力超负荷反应中，miR-132/212基因敲除小鼠的心脏功能恶化减弱。通过结合生化方法和检测，我们证实miR-132/212通过靶向SERCA2a的3'-末端非翻译区来调节SERCA2a。此外，我们还证实PTEN是miR-132/212的直接靶点，并可能参与对miR132/212的心脏反应。在终末期心力衰竭患者中，miR-132/212上调并与SERCA2a表达降低相关。心力衰竭中miR-132/212的上调通过靶向SERCA2a损害心脏收缩功能，提示对miR-132/212的药物抑制可能是促进心力衰竭患者心脏功能的一种有前景的治疗方法。
