title: Interstitial remodeling in beta1-adrenergic receptor transgenic mice.
abstract: BACKGROUND
  Inhibition of proteolytic MMP activity could be a therapeutic approach to prevent ventricular dilatation by diminishing collagen matrix turnover and interstitial fibrosis. We investigated the time-course of MMP/TIMP activity during transition from hypertrophy to ventricular dilatation in transgenic mice with myocyte overexpression of the human beta1-adrenergic receptor (beta1TG). These beta1TG mice were studied at 3 (normal function), 5 (hypertrophy) and 12 (ventricular dilatation) months of age compared to age-matched controls (WT).
  
  
  METHODS
  Picro Sirius red staining and real-time PCR were performed for total collagen and for collagen type I and III quantification, respectively. MMP-activity assays (zymography), immunoblotting and real-time PCR experiments were done for gelatinase- (MMP-2, -9), collagenase- (MMP-1, -13), membrane-type MMP- (MT1- MMP; MMP-14) and TIMP expression measurements. To investigate beta1-integrin activity, integrin-linked kinase (ILK) expression was measured by immunoblotting.
  
  
  RESULTS
  Compared to WT with normal cardiac function, interstitial collagen type I and III mRNA and protein expression increased 3.6-fold in beta1TG at 5 months of age with moderate fibrosis and cardiomyocyte hypertrophy and 17-fold in beta1TG at 12 months of age with severe fibrosis and ventricular dilatation. Protein expression of the collagenases MMP-1 and -13 as well as the gelatinase proMMP-2 increased in the beta1TG group with cardiac hypertrophy. Maximal activity of the gelatinase MMP-2 (3.5-fold vs.WT) was measured in beta1TG at 12 months of age with severe fibrosis and ventricular dilatation, accompanied by coexpression of MT1- MMP (3.8-fold vs.WT) colocalized to the cell membranes.
  
  
  CONCLUSIONS
  These data provide evidence that sympathetic overactivation can trigger interstitial matrix remodeling and fibrosis by induction of MMP/TIMP activity. In particular gelatinolytic MMP-2 activity accompanies ventricular dilatation and the development of heart failure.
authors.affiliation: Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes Klinik für Innere Medizin III, 66421, Homburg/Saar, Germany. seeland@med-in.uni-sb.de
authors.forename: Ute
authors.initials: U
authors.lastname: Seeland
authors.forename: Simina
authors.initials: S
authors.lastname: Selejan
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.forename: Patrick
authors.initials: P
authors.lastname: Müller
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D000099200:Scaffold Protein ILK
chemical_list: D003094:Collagen; D017364:Collagenases; D020782:Matrix Metalloproteinases; D017346:Protein Serine-Threonine Kinases; D018342:Receptors, Adrenergic, beta-1; D019714:Tissue Inhibitor of Metalloproteinases; D000099200:Scaffold Protein ILK