Cardiac remodeling and MMPs on the model of chronic daunorubicin-induced cardiomyopathy in rabbits

The matrix metalloproteinases (MMPs) play a key role duringcardiac remodeling. The aim of the study was to investigate thechanges in collagenous proteins and MMPs in the model ofnon-ischemic, anthracycline-induced chronic cardiomyopathy inrabbits using both biochemical and histological approaches. Thestudy 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 thecardioprotectant dexrazoxane (60 mg/kg, before eachdaunorubicin). Morphological changes in the myocardium ofdaunorubicin-treated animals were characterized by focalmyocardial interstitial fibrosis of different intensity. Thesubsequent proliferation of the fibrotic tissue was marked by anincreased content of both collagen types I and III, which resultedin their typical coexpression in the majority of bundles of fibersforming either smaller or larger scars. Biochemical analysisshowed a significantly increased concentration of hydroxyproline,mainly in the pepsin-insoluble fraction of collagenous proteins, inthe daunorubicin-treated group (1.42±0.12 mg/g) as comparedwith the control (1.03±0.04 mg/g) and dexrazoxane (1.07±0.07mg/g) groups. Dexrazoxane co-administration remarkablyreduced the cardiotoxic effects of daunorubicin to the extentcomparable with the controls in all evaluated parameters. Usingzymography, it was possible to detect only a gelatinolytic bandcorresponding to MMP-2 (MMP-9 activity was not detectable).However, no significant changes in MMP-2 activity weredetermined between individual groups. Immunohistochemicalanalysis revealed increased MMP-2 expression in bothcardiomyocytes and fibroblasts. Thus, this study has revealedspecific alterations in the collagen network in chronicanthracycline cardiotoxicity in relationship to the expression andactivity of major MMPs.