Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction.
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.
Li
Jun
J
Department of Internal Medicine II, University Hospital Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, D-12200, Berlin, Germany.
Schwimmbeck
Peter Lothar
PL
Tschope
Carsten
C
Leschka
Sebastian
S
Husmann
Lars
L
Rutschow
Susanne
S
Reichenbach
Florian
F
Noutsias
Michel
M
Kobalz
Ursula
U
Poller
Wolfgang
W
Spillmann
Frank
F
Zeichhardt
Heinz
H
Schultheiss
Heinz-Peter
HP
Pauschinger
Matthias
M
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
D016207:Cytokines; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D020782:Matrix Metalloproteinases