Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig. 2009

Andreas Goetzenich, and Nima Hatam, and Alma Zernecke, and Christian Weber, and Tanja Czarnotta, and Rüdiger Autschbach, and Stefan Christiansen
Department of Cardiothoracic Surgery, University of Aachen, Aachen, Germany. agoetzenich@ukaachen.de

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.

UI MeSH Term Description Entries
D009206 Myocardium The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow. Muscle, Cardiac,Muscle, Heart,Cardiac Muscle,Myocardia,Cardiac Muscles,Heart Muscle,Heart Muscles,Muscles, Cardiac,Muscles, Heart
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004317 Doxorubicin Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN. Adriamycin,Adriablastin,Adriablastine,Adriblastin,Adriblastina,Adriblastine,Adrimedac,DOXO-cell,Doxolem,Doxorubicin Hexal,Doxorubicin Hydrochloride,Doxorubicin NC,Doxorubicina Ferrer Farm,Doxorubicina Funk,Doxorubicina Tedec,Doxorubicine Baxter,Doxotec,Farmiblastina,Myocet,Onkodox,Ribodoxo,Rubex,Urokit Doxo-cell,DOXO cell,Hydrochloride, Doxorubicin,Urokit Doxo cell
D005109 Extracellular Matrix A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. Matrix, Extracellular,Extracellular Matrices,Matrices, Extracellular
D006333 Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (VENTRICULAR DYSFUNCTION), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as MYOCARDIAL INFARCTION. Cardiac Failure,Heart Decompensation,Congestive Heart Failure,Heart Failure, Congestive,Heart Failure, Left-Sided,Heart Failure, Right-Sided,Left-Sided Heart Failure,Myocardial Failure,Right-Sided Heart Failure,Decompensation, Heart,Heart Failure, Left Sided,Heart Failure, Right Sided,Left Sided Heart Failure,Right Sided Heart Failure
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013552 Swine Any of various animals that constitute the family Suidae and comprise stout-bodied, short-legged omnivorous mammals with thick skin, usually covered with coarse bristles, a rather long mobile snout, and small tail. Included are the genera Babyrousa, Phacochoerus (wart hogs), and Sus, the latter containing the domestic pig (see SUS SCROFA). Phacochoerus,Pigs,Suidae,Warthogs,Wart Hogs,Hog, Wart,Hogs, Wart,Wart Hog
D018487 Ventricular Dysfunction, Left A condition in which the LEFT VENTRICLE of the heart was functionally impaired. This condition usually leads to HEART FAILURE; MYOCARDIAL INFARCTION; and other cardiovascular complications. Diagnosis is made by measuring the diminished ejection fraction and a depressed level of motility of the left ventricular wall. LV Diastolic Dysfunction,LV Dysfunction,LV Systolic Dysfunction,Left Ventricular Diastolic Dysfunction,Left Ventricular Dysfunction,Left Ventricular Systolic Dysfunction,Diastolic Dysfunction, LV,Dysfunction, LV,Dysfunction, LV Diastolic,Dysfunction, LV Systolic,Dysfunction, Left Ventricular,LV Diastolic Dysfunctions,LV Dysfunctions,LV Systolic Dysfunctions,Left Ventricular Dysfunctions,Systolic Dysfunction, LV
D019715 Tissue Inhibitor of Metalloproteinase-1 A member of the family of TISSUE INHIBITOR OF METALLOPROTEINASES. It is a N-glycosylated protein, molecular weight 28 kD, produced by a vast range of cell types and found in a variety of tissues and body fluids. It has been shown to suppress metastasis and inhibit tumor invasion in vitro. TIMP-1,Metalloproteinase-1 Tissue Inhibitor,Tissue Inhibitor of Metalloproteinase 1

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