Involvement of furin-like proprotein convertases in the arterial response to injury

Abstract

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, α1-antitrypsin Portland (α1-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 α1-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 (PConclusions: 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.