Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Medzikovic, Lejla, Heese, Hylja, van Loenen, Pieter B., van Roomen, Cindy P. A. A., Hooijkaas, Ingeborg B., Christoffels, Vincent M., Creemers, Esther E., de Vries, Carlie J. M., de Waard, Vivian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915046/
https://www.ncbi.nlm.nih.gov/pubmed/33562500
http://dx.doi.org/10.3390/ijms22041600
_version_ 1783657146116734976
author Medzikovic, Lejla
Heese, Hylja
van Loenen, Pieter B.
van Roomen, Cindy P. A. A.
Hooijkaas, Ingeborg B.
Christoffels, Vincent M.
Creemers, Esther E.
de Vries, Carlie J. M.
de Waard, Vivian
author_facet Medzikovic, Lejla
Heese, Hylja
van Loenen, Pieter B.
van Roomen, Cindy P. A. A.
Hooijkaas, Ingeborg B.
Christoffels, Vincent M.
Creemers, Esther E.
de Vries, Carlie J. M.
de Waard, Vivian
author_sort Medzikovic, Lejla
collection PubMed
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.
format Online
Article
Text
id pubmed-7915046
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-79150462021-03-01 Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes Medzikovic, Lejla Heese, Hylja van Loenen, Pieter B. van Roomen, Cindy P. A. A. Hooijkaas, Ingeborg B. Christoffels, Vincent M. Creemers, Esther E. de Vries, Carlie J. M. de Waard, Vivian Int J Mol Sci Article 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. MDPI 2021-02-05 /pmc/articles/PMC7915046/ /pubmed/33562500 http://dx.doi.org/10.3390/ijms22041600 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Medzikovic, Lejla
Heese, Hylja
van Loenen, Pieter B.
van Roomen, Cindy P. A. A.
Hooijkaas, Ingeborg B.
Christoffels, Vincent M.
Creemers, Esther E.
de Vries, Carlie J. M.
de Waard, Vivian
Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915046/
https://www.ncbi.nlm.nih.gov/pubmed/33562500
http://dx.doi.org/10.3390/ijms22041600
work_keys_str_mv AT medzikoviclejla nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes
AT heesehylja nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes
AT vanloenenpieterb nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes
AT vanroomencindypaa nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes
AT hooijkaasingeborgb nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes
AT christoffelsvincentm nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes
AT creemersesthere nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes
AT devriescarliejm nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes
AT dewaardvivian nuclearreceptornur77controlscardiacfibrosisthroughdistinctactionsonfibroblastsandcardiomyocytes