TY - JOUR
T1 - Nuclear receptor nur77 controls cardiac fibrosis through distinct actions on fibroblasts and cardiomyocytes
AU - Medzikovic, Lejla
AU - Heese, Hylja
AU - van Loenen, Pieter B.
AU - van Roomen, Cindy P. A. A.
AU - Hooijkaas, Ingeborg B.
AU - Christoffels, Vincent M.
AU - Creemers, Esther E.
AU - de Vries, Carlie J. M.
AU - de Waard, Vivian
N1 - Funding Information: Funding: This research was funded by the Dutch Heart Foundation CVON 2014-11 RECONNECT (L.M.) and the Out of the Box grant 2017 from the Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands (V.d.W.). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - Cardiac
KW - Cardiomyocyte
KW - Fibroblast
KW - Fibrosis
KW - Myofibroblast
KW - Nuclear receptor
KW - Transforming growth factor β
UR - http://www.scopus.com/inward/record.url?scp=85100347220&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms22041600
DO - https://doi.org/10.3390/ijms22041600
M3 - Article
C2 - 33562500
SN - 1661-6596
VL - 22
SP - 1
EP - 16
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 4
M1 - 1600
ER -