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

• Published in: Cardiovascular research 2005-10, Vol.68 (1), p.136-143
• Main Authors: SLUIJTER, Joost P. G, VERLOOP, Robert E, PULSKENS, Wilco P. C, VELEMA, Evelyn, GRIMBERGEN, Jos M, QUAX, Paul H, GOUMANS, Marie-José, PASTERKAMP, Gerard, DE KLEIJN, Dominique P. V
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; alpha 1-Antitrypsin - genetics; Animals; Atherosclerosis - metabolism; Biological and medical sciences; Cardiology. Vascular system; Catheterization; Enzyme Activation; Femoral Artery - injuries; Femoral Artery - metabolism; Furin - antagonists & inhibitors; Furin - physiology; Genetic Vectors - administration & dosage; Iliac Artery - injuries; Iliac Artery - metabolism; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinases - metabolism; Matrix Metalloproteinases, Membrane-Associated; Medical sciences; Models, Animal; Rabbits; Smad Proteins, Receptor-Regulated - metabolism; Transduction, Genetic - methods; Transforming Growth Factor beta - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/j.cardiores.2005.05.016

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. 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