Published in:
Open Access 01-03-2007 | ORIGINAL CONTRIBUTION
Interstitial remodeling in β1-adrenergic receptor transgenic mice
Published in: Basic Research in Cardiology | Issue 2/2007
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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 β1-adrenergic receptor (β1TG). These β1TG 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 β1-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 β1TG at 5 months of age with moderate fibrosis and cardiomyocyte
hypertrophy and 17-fold in β1TG 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 β1TG
group with cardiac hypertrophy. Maximal activity of the gelatinase MMP-2
(3.5-fold vs.WT) was measured in β1TG 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.