Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig.
BACKGROUND
Anthracyclines are widely used in oncogenic therapy. Owing to their cardiotoxic side effects, their application is subdued to dose limitations. Many cardioprotective approaches have failed. This study examined the role of matrix metalloproteinases (MMP) in the remodeling process of extracellular matrix after treatment with doxorubicin (Adriamycin) as a toehold for a new therapeutic approach, for example, treatment with MMP inhibitors.


METHODS
Severe heart failure was induced in 6 pigs by the repetitive intracoronary application of Adriamycin. Degree of dilatation and insufficiency were measured by echocardiography and hemodynamics. Before and after treatment, MMP activity (fluorogenic assay: MMP-1, MMP-2) and gene expression (reverse transcription-polymerase chain reaction [RT-PCR]: MMP-1, -2, -9; membrane type-1 matrix metalloproteinase, [MT1MMP]; tissue inhibitor of metalloproteinase 1 [TIMP-1]) were measured. Spatial distribution of MMP-1, MMP-2, and collagen were visualized in antibody-stained frozen sections. One-way analysis of variance was used for data analysis.


RESULTS
Severe myocardial insufficiency (ejection fractions < 50% of baseline values) developed in all animals. No severe side effects were encountered. We found a strong activation of MMP-1 and MMP-2 in fluorogenic and PCR assays. RT-PCR revealed a significant activation of MMP-9 and MT1-MMP and a weaker induction of TIMP-1. Histology showed typical signs of myocardial fibrosis, with myocardial cell loss, collagen disorder, and vacuoles.


CONCLUSIONS
We showed a strong transcriptional activation for several specific MMPs in Adriamycin-induced cardiac remodeling. Contrary to published data on myocardial infarction, early inhibitory therapy before myocardial injury is possible in Adriamycin-treated patients. Local application by our catheter-based system would additionally help to avoid systemic side effects.
Goetzenich
Andreas
A
Department of Cardiothoracic Surgery, University of Aachen, Aachen, Germany. agoetzenich@ukaachen.de
Hatam
Nima
N
Zernecke
Alma
A
Weber
Christian
C
Czarnotta
Tanja
T
Autschbach
Rüdiger
R
Christiansen
Stefan
S
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D005109:Extracellular Matrix / Q000378:metabolism*; D006333:Heart Failure / Q000139:chemically induced* / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D013552:Swine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000378:metabolism*
D019715:Tissue Inhibitor of Metalloproteinase-1; D004317:Doxorubicin; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1