PubMed · 4214421
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L Ose. 1974-10-30. [Routine methods for fibrinogen determination].. https://pubmed.ncbi.nlm.nih.gov/4214421/
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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. METHODS AND 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.
The rate of activation of Glu-plasminogen by t-PA on fibrin clot and on the complexes of fibrinogen, its fragment X2, fibrin fragment D-D with N-DSK of fibrin has been studied. The reaction rate constant of (kcat/Km) increased and Km decreased in series of effectors X2-->X2 - N-DSK-->D-D-->D-D - N-DSK = fibrinogen - N-DSK-->fibrin clots. The structure of activator complexes of reaction of Glu-plasminogen activation by t-PA on fibrin clot has been suggested.
The fibrinolytic system contains a proenzyme plasminogen (Plg) which is converted to plasmin (Plm) by the action of Plg activators. Physiological Plg activators are: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plg was shown to be further cleaved by leukocyte elastase producing several fragments, one of which is called mini-plasminogen (mini-Plg) or neo-plasminogen Val442. In this paper we studied whether mini-Plg is able to produce clot lysis when it is activated by rt-PA in purified systems and in Plg depleted normal plasma. We found that mini-Plg clot lysis time was longer than that of Plg. Clot lysis times were 2.3 minutes +/- 0.06 for Plg and 9.8 minutes +/- 0.1 for mini-Plg. Mini-Plg is less efficient than Plg in producing clot lysis at all studied concentrations (0.1-1.2 microM). In Plg depleted normal human plasma mini-Plg is unable to produce complete clot lysis in presence of rt-PA. Although mini-Plg can be activated to mini-Plm by rt-PA, these results show that the activation process is insufficient to produce an efficient clot lysis.