The matrix metalloproteinases (MMPs) play a key role during
cardiac remodeling. The aim of the study was to investigate the
changes in collagenous proteins and MMPs in the model of
non-ischemic, anthracycline-induced chronic cardiomyopathy in
rabbits using both biochemical and histological approaches. The
study was carried out in three groups of Chinchilla male rabbits:
1) daunorubicin (3 mg/kg, once weekly for 10 weeks), 2) control
(saline in the same schedule), 3) daunorubicin with the
cardioprotectant dexrazoxane (60 mg/kg, before each
daunorubicin). Morphological changes in the myocardium of
daunorubicin-treated animals were characterized by focal
myocardial interstitial fibrosis of different intensity. The
subsequent proliferation of the fibrotic tissue was marked by an
increased content of both collagen types I and III, which resulted
in their typical coexpression in the majority of bundles of fibers
forming either smaller or larger scars. Biochemical analysis
showed a significantly increased concentration of hydroxyproline,
mainly in the pepsin-insoluble fraction of collagenous proteins, in
the daunorubicin-treated group (1.42±0.12 mg/g) as compared
with the control (1.03±0.04 mg/g) and dexrazoxane (1.07±0.07
mg/g) groups. Dexrazoxane co-administration remarkably
reduced the cardiotoxic effects of daunorubicin to the extent
comparable with the controls in all evaluated parameters. Using
zymography, it was possible to detect only a gelatinolytic band
corresponding to MMP-2 (MMP-9 activity was not detectable).
However, no significant changes in MMP-2 activity were
determined between individual groups. Immunohistochemical
analysis revealed increased MMP-2 expression in both
cardiomyocytes and fibroblasts. Thus, this study has revealed
specific alterations in the collagen network in chronic
anthracycline cardiotoxicity in relationship to the expression and
activity of major MMPs.
Reprint of “The complex dynamics of myocardial interstitial fibrosis in heart failure. Focus on collagen cross-linking”