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- Title
Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-β1 involves furin-convertase
- Authors
Stawowy, Philipp; Margeta, Christian; Kallisch, Heike; Seidah, Nabil G.; Chrétien, Michel; Fleck, Eckart; Graf, Kristof
- Abstract
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.
- Subjects
METALLOPROTEINASES; CYTOKINES; EXTRACELLULAR matrix; FIBROBLASTS
- Publication
Cardiovascular Research, 2004, Vol 63, Issue 1, p87
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1016/j.cardiores.2004.03.010