Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes
Open Access
- 5 February 2021
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 22 (4), 1600
- https://doi.org/10.3390/ijms22041600
Abstract
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.Funding Information
- Dutch Heart Foundation (CVON 2014-11 RECONNECT, Out of the Box grant 2017)
This publication has 40 references indexed in Scilit:
- Adrenergic Nervous System in Heart FailureCirculation Research, 2013
- Low-density lipoprotein receptor gene transfer in hypercholesterolemic mice improves cardiac function after myocardial infarctionGene Therapy, 2011
- Cardiac Rupture in Takotsubo Cardiomyopathy: A Systematic ReviewClinical Cardiology, 2011
- The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C− monocytesNature Immunology, 2011
- Mitochondrial translocation of Nur77 mediates cardiomyocyte apoptosisEuropean Heart Journal, 2011
- Nuclear receptor Nur77 inhibits vascular outward remodelling and reduces macrophage accumulation and matrix metalloproteinase levelsCardiovascular Research, 2010
- TGFβ, cardiac fibroblasts, and the fibrotic responseCardiovascular Research, 2007
- Structural and functional characterisation of cardiac fibroblastsCardiovascular Research, 2005
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003
- Chronic β2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanismCardiovascular Research, 2003