title: Lack of collagen VIII reduces fibrosis and promotes early mortality and cardiac dilatation in pressure overload in mice.
abstract: OBJECTIVE
  In pressure overload, left ventricular (LV) dilatation is a key step in transition to heart failure (HF). We recently found that collagen VIII (colVIII), a non-fibrillar collagen and extracellular matrix constituent, was reduced in hearts of mice with HF and correlated to degree of dilatation. A reduction in colVIII might be involved in LV dilatation, and we here examined the role of reduced colVIII in pressure overload-induced remodelling using colVIII knock-out (col8KO) mice.
  
  
  RESULTS
  Col8KO mice exhibited increased mortality 3-9 days after aortic banding (AB) and increased LV dilatation from day one after AB, compared with wild type (WT). LV dilatation remained increased over 56 days. Forty-eight hours after AB, LV expression of main structural collagens (I and III) was three-fold increased in WT mice, but these collagens were unaltered in the LV of col8KO mice together with reduced expression of the pro-fibrotic cytokine TGF-β, SMAD2 signalling, and the myofibroblast markers Pxn, α-SMA, and SM22. Six weeks after AB, LV collagen mRNA expression and protein were increased in col8KO mice, although less pronounced than in WT. In vitro, neonatal cardiac fibroblasts from col8KO mice showed lower expression of TGF-β, Pxn, α-SMA, and SM22 and reduced migratory ability possibly due to increased RhoA activity and reduced MMP2 expression. Stimulation with recombinant colVIIIα1 increased TGF-β expression and fibroblast migration.
  
  
  CONCLUSIONS
  Lack of colVIII reduces myofibroblast differentiation and fibrosis and promotes early mortality and LV dilatation in response to pressure overload in mice.
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Kirkeveien 166, Oslo 0407, Norway Faculty of Medicine, University of Oslo, Oslo, Norway KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Biljana
authors.initials: B
authors.lastname: Skrbic
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Kirkeveien 166, Oslo 0407, Norway Faculty of Medicine, University of Oslo, Oslo, Norway KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Kristin V T
authors.initials: KV
authors.lastname: Engebretsen
authors.affiliation: KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Mari E
authors.initials: ME
authors.lastname: Strand
authors.affiliation: KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway Department of Genetics, Harvard` Medical School, Boston, MA, USA.
authors.forename: Ida G
authors.initials: IG
authors.lastname: Lunde
authors.affiliation: KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Herum
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Kirkeveien 166, Oslo 0407, Norway KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Henriette S
authors.initials: HS
authors.lastname: Marstein
authors.affiliation: Faculty of Medicine, University of Oslo, Oslo, Norway KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Per K
authors.initials: PK
authors.lastname: Lunde
authors.affiliation: KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Cathrine R
authors.initials: CR
authors.lastname: Carlson
authors.affiliation: Faculty of Medicine, University of Oslo, Oslo, Norway KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Kirkeveien 166, Oslo 0407, Norway KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bjørnstad
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Kirkeveien 166, Oslo 0407, Norway Faculty of Medicine, University of Oslo, Oslo, Norway KG Jebsen Centre for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway theis.tonnessen@medisin.uio.no theistonnessen@hotmail.com thto@uus.no.
authors.forename: Theis
authors.initials: T
authors.lastname: Tønnessen
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D024102:Collagen Type VIII / Q000172:deficiency* / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis / Q000517:prevention & control; D006333:Heart Failure / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000502:physiology; D020742:rhoA GTP-Binding Protein
chemical_list: D024102:Collagen Type VIII; D016212:Transforming Growth Factor beta; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: Aortic banding; Collagen; Extracellular matrix; Heart failure; Remodelling