miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a
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 identi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2021.592362/full |
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| author | Zhiyong Lei Zhiyong Lei Christine Wahlquist Hamid el Azzouzi Janine C. Deddens Diederik Kuster Alain van Mil Alain van Mil Agustin Rojas-Munoz Manon M. Huibers Mark Mercola Roel de Weger Jolanda Van der Velden Junjie Xiao Junjie Xiao Pieter A. Doevendans Pieter A. Doevendans Pieter A. Doevendans Joost P. G. Sluijter Joost P. G. Sluijter |
| author_facet | Zhiyong Lei Zhiyong Lei Christine Wahlquist Hamid el Azzouzi Janine C. Deddens Diederik Kuster Alain van Mil Alain van Mil Agustin Rojas-Munoz Manon M. Huibers Mark Mercola Roel de Weger Jolanda Van der Velden Junjie Xiao Junjie Xiao Pieter A. Doevendans Pieter A. Doevendans Pieter A. Doevendans Joost P. G. Sluijter Joost P. G. Sluijter |
| author_sort | Zhiyong Lei |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T17:41:45Z |
| format | Article |
| id | doaj.art-e8911eb526d44c128a96bcd2108ada95 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-16T17:41:45Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-e8911eb526d44c128a96bcd2108ada952022-12-21T22:22:35ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2021-03-01810.3389/fcvm.2021.592362592362miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2aZhiyong Lei0Zhiyong Lei1Christine Wahlquist2Hamid el Azzouzi3Janine C. Deddens4Diederik Kuster5Alain van Mil6Alain van Mil7Agustin Rojas-Munoz8Manon M. Huibers9Mark Mercola10Roel de Weger11Jolanda Van der Velden12Junjie Xiao13Junjie Xiao14Pieter A. Doevendans15Pieter A. Doevendans16Pieter A. Doevendans17Joost P. G. Sluijter18Joost P. G. Sluijter19Experimental Cardiology Laboratory, Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, NetherlandsDivision Lab, Central Diagnosis Laboratory Research, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford Cardiovascular Institute, Stanford, CA, United StatesExperimental Cardiology Laboratory, Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, NetherlandsExperimental Cardiology Laboratory, Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Physiology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam Cardiovascular Sciences, Amsterdam, NetherlandsExperimental Cardiology Laboratory, Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, NetherlandsUniversity Medical Center Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford Cardiovascular Institute, Stanford, CA, United StatesDepartment of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford Cardiovascular Institute, Stanford, CA, United StatesDepartment of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Physiology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam Cardiovascular Sciences, Amsterdam, NetherlandsRegeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, ChinaSchool of Medicine, Shanghai University, Shanghai, ChinaExperimental Cardiology Laboratory, Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, NetherlandsNetherlands Heart Institute, Utrecht, Netherlands0Central Military Hospital Utrecht, Utrecht, NetherlandsExperimental Cardiology Laboratory, Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, NetherlandsUniversity Medical Center Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, University Medical Center Utrecht, Utrecht, NetherlandsCompromised 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.https://www.frontiersin.org/articles/10.3389/fcvm.2021.592362/fullmiR-132/212 familycardiac contractilityheart failuremyocardial infarctionknockout mice |
| spellingShingle | Zhiyong Lei Zhiyong Lei Christine Wahlquist Hamid el Azzouzi Janine C. Deddens Diederik Kuster Alain van Mil Alain van Mil Agustin Rojas-Munoz Manon M. Huibers Mark Mercola Roel de Weger Jolanda Van der Velden Junjie Xiao Junjie Xiao Pieter A. Doevendans Pieter A. Doevendans Pieter A. Doevendans Joost P. G. Sluijter Joost P. G. Sluijter miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a Frontiers in Cardiovascular Medicine miR-132/212 family cardiac contractility heart failure myocardial infarction knockout mice |
| title | miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a |
| title_full | miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a |
| title_fullStr | miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a |
| title_full_unstemmed | miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a |
| title_short | miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a |
| title_sort | mir 132 212 impairs cardiomyocytes contractility in the failing heart by suppressing serca2a |
| topic | miR-132/212 family cardiac contractility heart failure myocardial infarction knockout mice |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2021.592362/full |
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