© 1999 European Society of Cardiology
Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation
a Unité INSERM U492, Faculté de Médecine 8 rue du Général Sarrail, 94010 Créteil, France
b Unité INSERM U421, Faculté de Médecine 8 rue du Général Sarrail, 94010 Créteil, France
c Unité INSERM U400, Faculté de Médecine 8 rue du Général Sarrail, 94010 Créteil, France
d Centre d'Etudes Nucléaires de Saclay 91191 Gif sur Yvette, France
e Service d'Anatomie Pathologie du Professeur Le Charpentier CHU Pitié-Salpétrière, 75013 Paris, France
f Service de Chirurgie Cardiaque du Professeur Gandjbakhch CHU Pitié-Salpétrière, 75013 Paris, France
* Corresponding author. Tel.: +33-1-49-81-36-25; fax: +33-1-48-98-17-77. E-mail address: lafuma{at}im3.inserm.fr
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Abstract |
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Background: End-stage of human dilated cardiomyopathy (DCM) is characterized by myocyte loss and fibrosis, and associated with ventricular dilatation and reduced cardiac function. Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) have been involved in the myocardial remodeling.
Aims: To evaluate the potential role of matrix gelatinases (MMP-2 and MMP-9) in DCM, the balance between gelatinases and TIMPs and the gelatinase localization were investigated in left free wall ventricles from six normal donors and six patients with DCM at the transplantation time.
Methods: TIMP-(1, 2, 3 and 4) mRNAs were analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). TIMP-1 and -2 protein content was assessed by ELISA. MMP-2 and MMP-9 expression were examined by zymography and immunological techniques.
Results: All TIMPs were down-regulated in DCM hearts, especially TIMP-1 (reduced by 80%). Gel zymography revealed similar activity of MMP-2 and MMP-9 in both tissues. By in situ zymography and immunohistochemistry, active and immunoreactive gelatinases were pericardiomyocyte in control hearts and intracardiomyocyte in DCM hearts. Intracellular MMPs were associated with sarcomeric structure in DCM. To estimate a putative role of these gelatinases, several sarcomeric contractile proteins were digested in vitro by purified active MMP-9. Only myosin-heavy chain was cleaved in vitro giving 180-, 120-, 80- and 20-kDa proteolytic fragments. In vivo, two major myosin-heavy chain proteolytic fragments (80 and 20 kDa) were detected by specific monoclonal antibody against myosin-heavy chain in DCM left ventricular homogenates, only.
Conclusions: Taken together, these data highly suggest that MMP-2 and MMP-9 may be involved in the disorganization of the contractile apparatus in DCM hearts.
Key Words: Dilated cardiomyopathy • Matrix metalloproteinases • Tissue inhibitors of matrix metalloproteinases • Myosin-heavy chain proteolysis
Received April 26, 1999; Revised July 14, 1999; Accepted August 9, 1999
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