Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes
Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myof...
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doaj-39513847d0d6451e869bd58e23897a432021-02-06T00:01:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01221600160010.3390/ijms22041600Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and CardiomyocytesLejla Medzikovic0Hylja Heese1Pieter B. van Loenen2Cindy P. A. A. van Roomen3Ingeborg B. Hooijkaas4Vincent M. Christoffels5Esther E. Creemers6Carlie J. M. de Vries7Vivian de Waard8Department of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biology, Amsterdam UMC, Location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biology, Amsterdam UMC, Location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Experimental Cardiology, Amsterdam UMC, Location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsFibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor–β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis.https://www.mdpi.com/1422-0067/22/4/1600cardiacfibroblastmyofibroblastfibrosisnuclear receptorcardiomyocyte |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lejla Medzikovic Hylja Heese Pieter B. van Loenen Cindy P. A. A. van Roomen Ingeborg B. Hooijkaas Vincent M. Christoffels Esther E. Creemers Carlie J. M. de Vries Vivian de Waard |
spellingShingle |
Lejla Medzikovic Hylja Heese Pieter B. van Loenen Cindy P. A. A. van Roomen Ingeborg B. Hooijkaas Vincent M. Christoffels Esther E. Creemers Carlie J. M. de Vries Vivian de Waard Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes International Journal of Molecular Sciences cardiac fibroblast myofibroblast fibrosis nuclear receptor cardiomyocyte |
author_facet |
Lejla Medzikovic Hylja Heese Pieter B. van Loenen Cindy P. A. A. van Roomen Ingeborg B. Hooijkaas Vincent M. Christoffels Esther E. Creemers Carlie J. M. de Vries Vivian de Waard |
author_sort |
Lejla Medzikovic |
title |
Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes |
title_short |
Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes |
title_full |
Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes |
title_fullStr |
Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes |
title_full_unstemmed |
Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes |
title_sort |
nuclear receptor nur77 controls cardiac fibrosis through distinct actions on fibroblasts and cardiomyocytes |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-02-01 |
description |
Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor–β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis. |
topic |
cardiac fibroblast myofibroblast fibrosis nuclear receptor cardiomyocyte |
url |
https://www.mdpi.com/1422-0067/22/4/1600 |
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