| Autor: |
Medzikovic L; Department of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA., Heese H; Department of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., van Loenen PB; Department of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., van Roomen CPAA; Department of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., Hooijkaas IB; Department of Medical Biology, Amsterdam UMC, Location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., Christoffels VM; Department of Medical Biology, Amsterdam UMC, Location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., Creemers EE; Department of Experimental Cardiology, Amsterdam UMC, Location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., de Vries CJM; Department of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., de Waard V; Department of Medical Biochemistry, Amsterdam University Medical Centers (Amsterdam UMC), Location Academic Medical Center (AMC), Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. |
| Abstrakt: |
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. |
