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Cardiovascular Research 2004 63(1):87-97; doi:10.1016/j.cardiores.2004.03.010
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-β1 involves furin-convertase

Philipp Stawowy*,a, Christian Margetaa, Heike Kallischa, Nabil G Seidahb, Michel Chrétienc, Eckart Flecka and Kristof Grafa

aDepartment of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany
bLaboratory of Biochemical Neuroendocrinology, Clinical Research Institute, Montréal, QC, Canada
cDiseases of Aging and Regional Protein Chemistry Centers, Ottawa Health Research Institute, University of Ottawa, ON, Canada

*Corresponding author. Tel.: +49-30-4593-2413; fax: +49-30-4593-2415. Email address: stawowy{at}dhzb.de

Objective: Heart failure is characterized by an imbalance of matrix synthesis/turnover, finally resulting in fibrosis. Cardiac myocytes and fibroblasts play a pivotal role in the remodeling process. Cardiac remodeling involves the expression of TGF-β1 and matrix metalloproteinases (MMPs) in cardiac fibroblasts (CFBs). Furin, a subtilisin/kexin-like proprotein convertase (PC), activates TGF-β1 and membrane-bound MT1-MMP, which facilitates pro-gelatinase A (MMP-2) activation. Even though several reports identified TGF-β1 as a pro-fibrotic cytokine in the heart, it increases MMP-activity and cell migration/invasion in several cell types. The present study was done to investigate the contribution of TGF-β1 and furin to CFBs MMP-activity and motility. Methods and results: Stimulation of CFBs from adult Sprague–Dawley rats with TGF-β1 (20 ng/ml) induced furin, but had no effect on the closely related PC5. Inhibition of furin inhibited angiotensin II-induced TGF-β1 activation, indicating that TGF-β1 amplifies its activating convertase in CFBs. Pretreatment of CFBs with TGF-β1 (20 ng/ml, 24 h) increased their migration by about two-fold (p<0.05), which was accompanied by an enhanced expression and activity of MT1-MMP and MMP-2. Brefeldin A (BFA), a Golgi-disturbing agent, inhibited MT1-MMP activation, indicating that it occurs in the trans-Golgi network (TGN), where furin is concentrated and colocalized with MT1-MMP. Inhibition of furin significantly inhibited TGF-β1-induced MT1-MMP/MMP-2 activation. Furthermore, inhibition of furin attenuated TGF-β1-enhanced migration on gelatin-coated membranes (p<0.05). This was comparable to the effects of the MMP-inhibitor GM6001, pointing out that MMPs are major mediators of TGF-β1-enhanced CFB motility. Conclusion: We demonstrate that TGF-β1 induces MMP-activity in CFBs, thereby facilitating CFBs motility. Furthermore, TGF-β1 amplifies its activating convertase furin, which is also required for MT1-MMP/MMP-2 activation in CFBs. Thus, furin is central for TGF-β1 and MT1-MMP activation and might be a novel target in cardiac remodeling.

KEYWORDS Growth factors; Matrix metalloproteinases; Extracellular matrix; Remodelling

Time for primary review 20 days


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