© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-β1 involves furin-convertase
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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Z. Kassiri, V. Defamie, M. Hariri, G. Y. Oudit, S. Anthwal, F. Dawood, P. Liu, and R. Khokha Simultaneous Transforming Growth Factor {beta}-Tumor Necrosis Factor Activation and Cross-talk Cause Aberrant Remodeling Response and Myocardial Fibrosis in Timp3-deficient Heart J. Biol. Chem., October 23, 2009; 284(43): 29893 - 29904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Spruill, A. S. Lowry, R. E. Stroud, C. E. Squires, I. M. Mains, E. C. Flack, C. Beck, J. S. Ikonomidis, A. J. Crumbley, P. J. McDermott, et al. Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1362 - C1373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-P. Hu, A. Dandapat, Y. Liu, P. L. Hermonat, and J. L. Mehta Blockade of hypoxia-reoxygenation-mediated collagen type I expression and MMP activity by overexpression of TGF-beta1 delivered by AAV in mouse cardiomyocytes Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1833 - H1838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fischoeder, H. Meyborg, D. Stibenz, E. Fleck, K. Graf, and P. Stawowy Insulin augments matrix metalloproteinase-9 expression in monocytes Cardiovasc Res, March 1, 2007; 73(4): 841 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Varon, F. Tatin, V. Moreau, E. Van Obberghen-Schilling, S. Fernandez-Sauze, E. Reuzeau, I. Kramer, and E. Genot Transforming Growth Factor {beta} Induces Rosettes of Podosomes in Primary Aortic Endothelial Cells. Mol. Cell. Biol., May 1, 2006; 26(9): 3582 - 3594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Manso, L. Elsherif, S.-M. Kang, and R. S. Ross Integrins, membrane-type matrix metalloproteinases and ADAMs: Potential implications for cardiac remodeling Cardiovasc Res, February 15, 2006; 69(3): 574 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Stawowy, C. Margeta, F. Blaschke, C. Lindschau, C. Spencer-Hansch, M. Leitges, G. Biagini, E. Fleck, and K. Graf Protein kinase C epsilon mediates angiotensin II-induced activation of {beta}1-integrins in cardiac fibroblasts Cardiovasc Res, July 1, 2005; 67(1): 50 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Stawowy, H. Meyborg, D. Stibenz, N. B. P. Stawowy, M. Roser, U. Thanabalasingam, J. P. Veinot, M. Chretien, N. G. Seidah, E. Fleck, et al. Furin-Like Proprotein Convertases Are Central Regulators of the Membrane Type Matrix Metalloproteinase-Pro-Matrix Metalloproteinase-2 Proteolytic Cascade in Atherosclerosis Circulation, May 31, 2005; 111(21): 2820 - 2827. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. O. Lee, J. L. Kang, and Y. H. Chong The Amyloid-{beta} Peptide Suppresses Transforming Growth Factor-{beta}1-induced Matrix Metalloproteinase-2 Production via Smad7 Expression in Human Monocytic THP-1 Cells J. Biol. Chem., March 4, 2005; 280(9): 7845 - 7853. [Abstract] [Full Text] [PDF]
|
|