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.
(2021) Frontiers in cardiovascular medicine, volume 8
(Article)
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,
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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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Keywords: cardiac contractility, heart failure, knockout mice, miR-132/212 family, myocardial infarction, Cardiology and Cardiovascular Medicine, Journal Article
ISSN: 2297-055X
Publisher: Frontiers Media S. A.
Note: Funding Information: This research was financed by Project P1.05 LUST of the research program of the Biomedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs and the Netherlands Cardiovascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, the Royal Netherlands Academy of Sciences, the National Institutes of Health USA (1RO1 HL113601), and the Leducq Shapeheart Transatlantic Alliance. This project was supported by the project EVICARE (No. 725229) of the European Research Council (ERC) to JS; by NWO-CAS grant (116006102) to PD and JS. National Institutes of Health (R01HL130840 and P01HL141084) and Fondation Leducq Transatlantic Alliance CURE-PLaN and support from the Joan and Sanford I. Weill Scholar Endowment to MM, American Heart Association (18CDA34070040) to CW. Funding Information: We would like to thank Dr. Taro Fukao (Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany) for miR-132/212 knockout mice; Corina Metz, Esther van Eeuwijk, and Maike Brans (University Medical Center Utrecht, the Netherlands) for their excellent technical assistance; Max Goebel (VU University Medical Center) for isolation, calcium imaging, and sarcomere shortening study in adult cardiomyocytes and Erica Siera-De Koning (University Medical Center Utrecht, the Netherlands) for the preparation of human patient materials. Funding. This research was financed by Project P1.05 LUST of the research program of the Biomedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs and the Netherlands Cardiovascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, the Royal Netherlands Academy of Sciences, the National Institutes of Health USA (1RO1 HL113601), and the Leducq Shapeheart Transatlantic Alliance. This project was supported by the project EVICARE (No. 725229) of the European Research Council (ERC) to JS; by NWO-CAS grant (116006102) to PD and JS. National Institutes of Health (R01HL130840 and P01HL141084) and Fondation Leducq Transatlantic Alliance CURE-PLaN and support from the Joan and Sanford I. Weill Scholar Endowment to MM, American Heart Association (18CDA34070040) to CW. Publisher Copyright: © Copyright © 2021 Lei, Wahlquist, el Azzouzi, Deddens, Kuster, van Mil, Rojas-Munoz, Huibers, Mercola, de Weger, Van der Velden, Xiao, Doevendans and Sluijter.
(Peer reviewed)
