Interstitial remodeling in beta1-adrenergic receptor transgenic mice.
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. CONCLUSION : 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.[1]References
- Interstitial remodeling in beta1-adrenergic receptor transgenic mice. Seeland, U., Selejan, S., Engelhardt, S., Müller, P., Lohse, M.J., Böhm, M. Basic Res. Cardiol. (2007) [Pubmed]
Annotations and hyperlinks in this abstract are from individual authors of WikiGenes or automatically generated by the WikiGenes Data Mining Engine. The abstract is from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.About WikiGenesOpen Access LicencePrivacy PolicyTerms of Useapsburg
