Plasminogen activator inhibitor-1 in neointima of vein grafts: its role in reduced fibrinolytic potential and graft failure.
BACKGROUND
Intimal smooth muscle cell proliferation is an underlying pathogenetic mechanism for neointimal hyperplasia and consequent vein graft failure. This study characterizes the expression of tissue-type plasminogen activator (TPA), urokinase-type plasminogen activator (UPA), and plasminogen activator inhibitor-1 (PAI-1) in hyperplastic vein grafts and normal venous tissue.


RESULTS
Failing graft and control vein specimens from 14 donors were homogenized, and TPA and PAI-1 were quantified with ELISA. The amount of PAI-1 was seven times higher (4.2+/-2.1 versus 0.6+/-0.6 ng/mg protein, P<.005), but the TPA antigen content was markedly lower (3.1+/-2.1 versus 8.1+/-3.7 ng/mg protein, P<.005) in the stenosed grafts compared with the control veins. Strong immunohistochemical PAI-1 reactivity and in situ hybridization signals for PAI-1 and UPA mRNA were associated with the smooth muscle cells of the thickened intima of the grafts. Functional assays of the graft specimens showed an increased UPA/TPA ratio and a decreased total fibrinolytic activity in comparison with normal veins.


CONCLUSIONS
Upregulation of PAI-1 mRNA expression and markedly increased amounts of PAI-1 antigen were detected in the vein grafts after the development of neointima. Furthermore, augmented UPA activity was found in the graft wall, but TPA was clearly depleted. Altogether, our findings imply decreased fibrinolytic potential in the stenosed graft, which may contribute to the graft occlusion.
Kauhanen
P
P
Wihuri Research Institute, Helsinki, Finland.
Sirén
V
V
Carpén
O
O
Vaheri
A
A
Lepäntalo
M
M
Lassila
R
R
D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000235:genetics / Q000494:pharmacology; D010960:Plasminogen Activators / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015842:Serine Proteinase Inhibitors / Q000032:analysis* / Q000235:genetics / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D017539:Tunica Intima / Q000737:chemistry* / Q000201:enzymology; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D014680:Veins / Q000737:chemistry / Q000201:enzymology / Q000637:transplantation*
D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D005337:Fibrin; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator