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

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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 (ptrans-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 (pConclusion: 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.

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