title: Ablation of biglycan attenuates cardiac hypertrophy and fibrosis after left ventricular pressure overload.
abstract: OBJECTIVE
  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.
  
  
  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: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Nadine
authors: N
authors: Beetz
authors: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors: Carolin
authors: C
authors: Rommel
authors: 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.
authors: Tilman
authors: T
authors: Schnick
authors: 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.
authors: Elena
authors: E
authors: Neumann
authors: 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.
authors: Achim
authors: A
authors: Lother
authors: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Elsa Beatriz
authors: EB
authors: Monroy-Ordonez
authors: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Martin
authors: M
authors: Zeeb
authors: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Sebastian
authors: S
authors: Preissl
authors: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Ralf
authors: R
authors: Gilsbach
authors: Institute for Pharmacology and Clinical Pharmacology, University of Düsseldorf, Düsseldorf, Germany.
authors: Ariane
authors: A
authors: Melchior-Becker
authors: Heart Center, Department of Cardiovascular Surgery, University of Freiburg, Freiburg, Germany.
authors: Bartosz
authors: B
authors: Rylski
authors: Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany.
authors: Monika
authors: M
authors: Stoll
authors: Pharmazentrum, Allgemeine Pharmakologie und Toxikologie, Goethe Universität, Frankfurt, Germany.
authors: Liliana
authors: L
authors: Schaefer
authors: Heart Center, Department of Cardiovascular Surgery, University of Freiburg, Freiburg, Germany.
authors: Friedhelm
authors: F
authors: Beyersdorf
authors: Heart Center, Department of Congenital Heart Defects and Pediatric Cardiology, University of Freiburg, Freiburg, Germany.
authors: Brigitte
authors: B
authors: Stiller
authors: 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.
authors: Lutz
authors: L
authors: Hein
mesh_terms: D000818:Animals; D058578:Biglycan / Q000172:deficiency* / Q000378:metabolism*; D006332:Cardiomegaly / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D005355:Fibrosis; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D020543:Proteome; D040901:Proteomics; D051381:Rats; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*; D020257:Ventricular Remodeling
chemical_list: D058578:Biglycan; D020543:Proteome
keywords: Biglycan; Cardiac hypertrophy; Heart failure; Proteoglycan