title: Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction.
abstract: OBJECTIVE
  Myocardial collagen degradation is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs). The possible relevance of MMPs in association with the inflammatory induction was investigated in a murine coxsackievirus B3 myocarditis model.
  
  
  METHODS
  Hearts from viral infected and sham-infected BALB/c mice were analyzed by semi-quantitative RT-PCR, picrosirius red staining, Western blot analysis, and immunohistochemistry.
  
  
  RESULTS
  In viral infected mice, both mRNA and protein abundance for collagen type I remained unaltered. In addition, picrosirius red staining showed the unchanged total collagen content. However, degraded soluble fraction of collagen type I protein was increased. Moreover, the mRNA abundance for MMP-3 and MMP-9 was upregulated, whereas the mRNAs for TIMP-1 and TIMP-4 were downregulated, respectively. The upregulation of MMP-3/MMP-9 and downregulation of TIMP-4 were confirmed at the protein level, and were associated with significantly increased mRNA levels of interleukin 1beta, tumor necrosis factor-alpha, transforming growth factor-beta1 and interleukin-4.
  
  
  CONCLUSIONS
  The increment of MMPs in the absence of counterbalance by TIMPs may lead to a functional defect of the myocardial collagen network by posttranslational mechanisms. This may contribute significantly to the development of left ventricular dysfunction in murine viral myocarditis. The inflammatory response with induction of cytokines may mediate the dysregulation of the myocardial MMP/TIMP systems.
authors.affiliation: Department of Internal Medicine II, University Hospital Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, D-12200, Berlin, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Peter Lothar
authors.initials: PL
authors.lastname: Schwimmbeck
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschope
authors.forename: Sebastian
authors.initials: S
authors.lastname: Leschka
authors.forename: Lars
authors.initials: L
authors.lastname: Husmann
authors.forename: Susanne
authors.initials: S
authors.lastname: Rutschow
authors.forename: Florian
authors.initials: F
authors.lastname: Reichenbach
authors.forename: Michel
authors.initials: M
authors.lastname: Noutsias
authors.forename: Ursula
authors.initials: U
authors.lastname: Kobalz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.forename: Frank
authors.initials: F
authors.lastname: Spillmann
authors.forename: Heinz
authors.initials: H
authors.lastname: Zeichhardt
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Matthias
authors.initials: M
authors.lastname: Pauschinger
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism*; D003384:Coxsackievirus Infections / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D006439:Hemodynamics; D007124:Immunoenzyme Techniques; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D020782:Matrix Metalloproteinases