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. 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.
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