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


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.
Sluijter
Joost P G
JP
Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands.
Verloop
Robert E
RE
Pulskens
Wilco P C
WP
Velema
Evelyn
E
Grimbergen
Jos M
JM
Quax
Paul H
PH
Goumans
Marie-José
MJ
Pasterkamp
Gerard
G
de Kleijn
Dominique P V
DP
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002404:Catheterization; D004789:Enzyme Activation; D005263:Femoral Artery / Q000293:injuries* / Q000378:metabolism; D045683:Furin / Q000037:antagonists & inhibitors / Q000502:physiology*; D005822:Genetic Vectors / Q000008:administration & dosage; D007083:Iliac Artery / Q000293:injuries* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D023421:Models, Animal; D011817:Rabbits; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics
D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; D000515:alpha 1-Antitrypsin; D045683:Furin; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2