Background: Furin-like proprotein convertases (PCs) are proteolytic activators of proproteins, like membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor beta (TGF-beta), that are described in the arterial response to injury. However, the involvement of furin-like PCs in the arterial response to injury has not been studied yet. We studied furin, MT1-MMP, MMP levels and TGF-beta signaling after arterial injury. We also investigated the effect of an inhibitor of furin-like PCs, alpha1-antitrypsin Portland (alpha1-PDX), on arterial injury following balloon dilation. Methods and results: NZW rabbit femoral and iliac arteries (N = 42) were balloon dilated unilaterally and harvested after 2, 7, 14, 28 or 42 days. Furin mRNA levels were increased after 2 and 7 days. MMP-2 and MT1-MMP levels were increased after day 7 and TGF-beta signaling, by phosphorylating Smad 1/5 and 2/3, was increased at all time points. Inhibition of furin-like PCs, by adenoviral over-expression of alpha1-PDX, blocked proTGF-beta activation and Smad phosphorylation, and reduced MT1-MMP and MMP-2 activation (N = 5). In vivo adventitial inhibition of furin-like PCs (N = 9) resulted in a reduction of 13.1 ± 5.2% in advential and 23.6 ± 7.9% in intimal areas (P < 0.05), but had no effect on lumen size due to decreased vessel areas. Conclusions: This study demonstrates that furin-like PCs are involved in the arterial response to injury possibly through activation of the TGF-beta-Smad signaling pathway and identifies furin-like PCs as a possible target to inhibit intimal hyperplasia. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. Chemicals / CAS: alpha 1 antitrypsin, 9041-92-3; gelatinase A, 146480-35-5; serine proteinase, 37259-58-8; Smad1 protein, 444952-89-0; Smad2 protein, 253862-89-4; Smad3 protein, 237417-78-6, 237417-96-8, 237418-00-7; Smad5 protein, 193228-56-7; alpha 1-Antitrypsin; Furin, EC 3.4.21.75; Matrix Metalloproteinase 2, EC 3.4.24.24; Matrix Metalloproteinases, EC 3.4.24.-; Matrix Metalloproteinases, Membrane-Associated, EC 3.4.24.-; Smad Proteins, Receptor-Regulated; Transforming Growth Factor beta