scholarly journals Inhibition of Pathological Retinal Neovascularization by a Small Peptide Derived from Human Tissue-Type Plasminogen Kringle 2

2020 ◽  
Vol 10 ◽  
Author(s):  
Qian Sun ◽  
Yinchen Shen ◽  
Li Su ◽  
Xun Xu
Keyword(s):  
Human Tissue ◽  
Retinal Neovascularization ◽  
Tissue Type ◽  
Small Peptide ◽  
Kringle 2

Properties of Chimeric (Tissue-Type/Urokinase-Type) Plasminogen Activators Obtained by Fusion at the Plasmin Cleavage Site

1993 ◽  
Vol 69 (05) ◽  
pp. 466-472 ◽  
Author(s):  
M Colucci ◽  
L G Cavallo ◽  
G Agnelli ◽  
A Mele ◽  
R Bürgi ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Plasminogen Activator ◽  
Cleavage Site ◽  
Plasminogen Activators ◽  
Tissue Type ◽  
Low Molecular Weight ◽  
Single Chain ◽  
Type Plasminogen Activator ◽  
Kringle 2 ◽  
Fibrin Monomers

SummaryTwo hybrid plasminogen activators (K2tu-PA and FK2tu-PA), linking the kringle 2 domain or the finger plus the kringle 2 domains of tissue-type plasminogen activator (t-PA) to the catalytic domain of single-chain urokinase-type plasminogen activator (scu-PA) were studied. At variance with similar constructs previously reported, they were obtained by fusion of the t-PA and scu-PA derived portions at their plasmin cleavage site (between Arg275 of t-PA and Ile159 of scu-PA), thus eliminating from scu-PA the two peptide bonds (Glu143-Leu144 and Arg156-Phe157) that lead to low molecular weight scu-PA and to thrombin-inactivated tcu-PA. The specific activities of K2tu-PA and FK2tu-PA, as measured by fibrin plate were 2.5 × 106 and 1.0 × 106 t-PA equivalent units/mg, respectively. Activation of plasminogen by hybrid PAs was stimulated by both CNBr-digested fibrinogen (40- and 80-fold) and Des-A-fibrin monomers (6- and 12-fold). The relatively weak stimulation of chimeric PAs by minimally degraded fibrin monomers was consistent with their reduced fibrin binding capacity. Like scu-PA, the chimeric PAs, in the single-chain form, were insensitive to inhibition, as they retained full activity after prolonged incubation in plasma and did not interact with SDS-reactivated recombinant PAI-1. The concentration producing 50% lysis of blood clots in 3 h was 0.5 μg/ml for K2tu-PA and 1 μg/ml for FK2tu-PA, as compared to 0.5 μg/ml and >2 μg/ml for t-PA and scu-PA, respectively. Plasminogen and α2-antiplasmin consumption induced by the hybrid PAs in clot-free plasma was comparable to (K2tu-PA) or lower than (FK2tu-PA) that induced by either t-PA or scu-PA. When exposed to plasmin, the hybrids were completely converted into two-chain molecules with full enzymatic activity. At variance with u-PA, however, the two-chain recombinant activators still required fibrin for full expression of activity. These data indicate that the products of such “artificial” fusion behave like true chimeras without loss of biological activity. The insensitivity to thrombin inactivation and to the proteolytic cleavage leading to low molecular weight scu-PA might confer enhanced stability to the molecules, especially at thrombus level. Moreover, if the thrombolytic activity observed in vitro is maintained in vivo, the prolonged half life of these hybrids should result in higher plasma levels of activator and thus in more extensive and rapid lysis.

scholarly journals Influence of fibrin and liver blood flow on the turnover and the systemic fibrinogenolytic effects of recombinant human tissue-type plasminogen activator in rabbits

Blood ◽  
1986 ◽  
Vol 67 (5) ◽  
pp. 1493-1497 ◽  
Author(s):  
H Bounameaux ◽  
JM Stassen ◽  
C Seghers ◽  
D Collen
Keyword(s):  
Blood Flow ◽  
Plasminogen Activator ◽  
Human Tissue ◽  
Femoral Vein ◽  
Liver Blood Flow ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Cardiovascular Failure ◽  
Type Plasminogen Activator ◽  
Impaired Liver

Abstract The influence of the presence of fibrin microclots on the systemic fibrinogenolytic effects of intravenous (IV) recombinant human tissue- type plasminogen activator (rt-PA) was studied by injection of a homogenized fibrin suspension in the femoral vein or artery in rabbits. A linear correlation (P less than .001) was found between the extent of fibrinogen breakdown and the amount of fibrin (0 to 32 mg/kg) injected just prior to the IV infusion of rt-PA at a rate of 10 micrograms/kg/min for 60 minutes. This finding suggests that the systemic activation of the fibrinolytic system observed in some patients during infusion of rt-PA may be due, at least in part, to the presence of fibrin in the vascular bed. The effect of blood flow in the liver on the turnover of rt-PA was measured in rabbits after ligation of the hepatic artery and monitoring of the blood flow in the portal vein with a peristaltic pump. The half-life (t1/2) of rt-PA in plasma was inversely correlated with the logarithm of the rate of the liver blood flow. A doubling of the plasma t1/2 of rt-PA was observed after an eightfold reduction of the liver blood flow, suggesting that delayed clearance of rt-PA may occur in patients with severe cardiovascular failure and impaired liver blood flow.

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