Nadine Beetz1, Carolin Rommel2, Tilman Schnick3, Elena Neumann3, Achim Lother4, Elsa Beatriz Monroy-Ordonez1, Martin Zeeb1, Sebastian Preissl1, Ralf Gilsbach1, Ariane Melchior-Becker5, Bartosz Rylski6, Monika Stoll7, Liliana Schaefer8, Friedhelm Beyersdorf6, Brigitte Stiller9, Lutz Hein10. 1. Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 2. Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. 3. Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Heart Center, Department of Congenital Heart Defects and Pediatric Cardiology, University of Freiburg, Freiburg, Germany. 4. Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Heart Center, Department of Cardiology and Angiology I, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 5. Institute for Pharmacology and Clinical Pharmacology, University of Düsseldorf, Düsseldorf, Germany. 6. Heart Center, Department of Cardiovascular Surgery, University of Freiburg, Freiburg, Germany. 7. Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany. 8. Pharmazentrum, Allgemeine Pharmakologie und Toxikologie, Goethe Universität, Frankfurt, Germany. 9. Heart Center, Department of Congenital Heart Defects and Pediatric Cardiology, University of Freiburg, Freiburg, Germany. 10. Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany. Electronic address: lutz.hein@pharmakol.uni-freiburg.de.
Abstract
AIMS: Biglycan, a small leucine-rich proteoglycan, has been shown to play an important role in stabilizing fibrotic scars after experimental myocardial infarction. However, the role of biglycan in the development and regression of cardiomyocyte hypertrophy and fibrosis during cardiac pressure overload and unloading remains elusive. Thus, the aim of the present study was to assess the effect of biglycan on cardiac remodeling in a mouse model of left ventricular pressure overload and unloading. METHODS AND RESULTS: Left ventricular pressure overload induced by transverse aortic constriction (TAC) in mice resulted in left ventricular dysfunction, fibrosis and increased biglycan expression. Fluorescence- and magnetic-assisted sorting of cardiac cell types revealed upregulation of biglycan in the fibroblast population, but not in cardiomyocytes, endothelial cells or leukocytes after TAC. Removal of the aortic constriction (rTAC) after short-term pressure overload (3weeks) improved cardiac contractility and reversed ventricular hypertrophy but not fibrosis in wild-type (WT) mice. Biglycan ablation (KO) enhanced functional recovery but did not resolve cardiac fibrosis. After long-term TAC for 9weeks, ablation of biglycan attenuated the development of cardiac hypertrophy and fibrosis. In vitro, biglycan induced hypertrophy of neonatal rat cardiomyocytes and led to activation of a hypertrophic gene program. Putative downstream mediators of biglycan signaling include Rcan1, Abra and Tnfrsf12a. These genes were concordantly induced by TAC in WT but not in biglycan KO mice. CONCLUSIONS: Left ventricular pressure overload induces biglycan expression in cardiac fibroblasts. Ablation of biglycan improves cardiac function and attenuates left ventricular hypertrophy and fibrosis after long-term pressure overload. In vitro biglycan induces hypertrophy of cardiomyocytes, suggesting that biglycan may act as a signaling molecule between cell types to modulate cardiac remodeling.
AIMS: Biglycan, a small leucine-rich proteoglycan, has been shown to play an important role in stabilizing fibrotic scars after experimental myocardial infarction. However, the role of biglycan in the development and regression of cardiomyocyte hypertrophy and fibrosis during cardiac pressure overload and unloading remains elusive. Thus, the aim of the present study was to assess the effect of biglycan on cardiac remodeling in a mouse model of left ventricular pressure overload and unloading. METHODS AND RESULTS: Left ventricular pressure overload induced by transverse aortic constriction (TAC) in mice resulted in left ventricular dysfunction, fibrosis and increased biglycan expression. Fluorescence- and magnetic-assisted sorting of cardiac cell types revealed upregulation of biglycan in the fibroblast population, but not in cardiomyocytes, endothelial cells or leukocytes after TAC. Removal of the aortic constriction (rTAC) after short-term pressure overload (3weeks) improved cardiac contractility and reversed ventricular hypertrophy but not fibrosis in wild-type (WT) mice. Biglycan ablation (KO) enhanced functional recovery but did not resolve cardiac fibrosis. After long-term TAC for 9weeks, ablation of biglycan attenuated the development of cardiac hypertrophy and fibrosis. In vitro, biglycan induced hypertrophy of neonatal rat cardiomyocytes and led to activation of a hypertrophic gene program. Putative downstream mediators of biglycan signaling include Rcan1, Abra and Tnfrsf12a. These genes were concordantly induced by TAC in WT but not in biglycan KO mice. CONCLUSIONS: Left ventricular pressure overload induces biglycan expression in cardiac fibroblasts. Ablation of biglycan improves cardiac function and attenuates left ventricular hypertrophy and fibrosis after long-term pressure overload. In vitro biglycan induces hypertrophy of cardiomyocytes, suggesting that biglycan may act as a signaling molecule between cell types to modulate cardiac remodeling.
Authors: Ralf Gilsbach; Martin Schwaderer; Sebastian Preissl; Björn A Grüning; David Kranzhöfer; Pedro Schneider; Thomas G Nührenberg; Sonia Mulero-Navarro; Dieter Weichenhan; Christian Braun; Martina Dreßen; Adam R Jacobs; Harald Lahm; Torsten Doenst; Rolf Backofen; Markus Krane; Bruce D Gelb; Lutz Hein Journal: Nat Commun Date: 2018-01-26 Impact factor: 14.919
Authors: Chandan K Nagaraju; Eef Dries; Natasa Popovic; Abhishek A Singh; Peter Haemers; H Llewelyn Roderick; Piet Claus; Karin R Sipido; Ronald B Driesen Journal: Sci Rep Date: 2017-09-07 Impact factor: 4.379