Copyright © 2005, European Society of Cardiology
Involvement of furin-like proprotein convertases in the arterial response to injury
aExperimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands
bInteruniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands
cGaubius Laboratory TNO-PG, Leiden, The Netherlands
dDepartment of Surgery, Leiden University Medical Center, Leiden, The Netherlands
* Corresponding author. University Medical Center, Experimental Cardiology Laboratory, Heidelberglaan 100, Room G02-523, 3584 CX Utrecht, The Netherlands. Tel.: +31 30 2507155; fax: +31 30 2522693. Email address: d.dekleijn{at}hli.azu.nl
Background: Furin-like proprotein convertases (PCs) are proteolytic activators of proproteins, like membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor β (TGF-β), 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-β signaling after arterial injury. We also investigated the effect of an inhibitor of furin-like PCs, 
1-antitrypsin Portland (1-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-β 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 1-PDX, blocked proTGF-β 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-β–Smad signaling pathway and identifies furin-like PCs as a possible target to inhibit intimal hyperplasia.
KEYWORDS Gene therapy; Remodeling; Balloon dilation; Transforming growth factor β (TGF-β); Matrix metalloproteinases
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