Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes
Autor: | Vincent M. Christoffels, Cindy P. A. A. van Roomen, Esther E. Creemers, Ingeborg B. Hooijkaas, Hylja Heese, Lejla Medzikovic, Vivian de Waard, Pieter B. van Loenen, Carlie J.M. de Vries |
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Přispěvatelé: | Medical Biochemistry, ACS - Heart failure & arrhythmias, Amsterdam Reproduction & Development (AR&D), Medical Biology, Cardiology, ACS - Diabetes & metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Atherosclerosis & ischemic syndromes |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Cardiac fibrosis Mice Knockout ApoE Heart Rupture cardiomyocyte 030204 cardiovascular system & hematology fibroblast Extracellular matrix lcsh:Chemistry Mice 0302 clinical medicine Fibrosis Transforming Growth Factor beta Nuclear Receptor Subfamily 4 Group A Member 1 Myocytes Cardiac nuclear receptor Myofibroblasts lcsh:QH301-705.5 Spectroscopy Cells Cultured Mice Knockout Ventricular Remodeling Models Cardiovascular General Medicine Computer Science Applications Cell biology Gene Knockdown Techniques cardiovascular system Intercellular Signaling Peptides and Proteins Collagen Cardiomyopathies Nerve growth factor IB cardiac Catalysis Article Inorganic Chemistry 03 medical and health sciences Paracrine signalling medicine Animals Physical and Theoretical Chemistry Molecular Biology Transforming growth factor β business.industry Myocardium Organic Chemistry Cardiac Rupture fibrosis Fibroblasts medicine.disease myofibroblast Rats Mice Inbred C57BL Disease Models Animal 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 Heart failure business Transforming growth factor |
Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 1600, p 1600 (2021) International journal of molecular sciences, 22(4):1600, 1-16. Multidisciplinary Digital Publishing Institute (MDPI) International Journal of Molecular Sciences Volume 22 Issue 4 |
ISSN: | 1661-6596 1422-0067 |
Popis: | 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. |
Databáze: | OpenAIRE |
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