Lipoprotein(a): a kinetic study of its influence on fibrin-dependent plasminogen activation by prourokinase or tissue plasminogen activator.
Lipoprotein(a) [Lp(a)] has been postulated to inhibit fibrinolysis due to its structural homology to plasminogen. Indeed, it has been reported that Lp(a) competitively inhibits the promotion by fibrin of tissue plasminogen activator (t-PA)-catalyzed plasminogen activation. However, it has also been reported that this inhibition is uncompetitive. No studies have been published, to our knowledge, of the effect of Lp(a) on prourokinase (pro-UK)-catalyzed plasminogen activation. Plasminogen activation by pro-UK or a plasmin-resistant mutant pro-UK was previously shown to be promoted by fibrin fragment E2, whereas that by t-PA is promoted by fragment D. Therefore, the influence of Lp(a) on the kinetics of these two reactions was examined. When Lp(a) was added (90-600 nM), no change in the rate of plasmin generation by Ala158-pro-UK was observed. Consistent with this, immobilized Lp(a) also failed to bind to fragment E2, whereas it did bind to D dimer. When t-PA-catalyzed plasminogen activation in the presence of D dimer was measured, uncompetitive inhibition by Lp(a) was found, but only at low concentrations of D dimer (< 0.5 microM) or t-PA (0.05 nM). At higher concentrations of D dimer and t-PA, instead of inhibition, Lp(a) induced a 2.4-fold promotion of plasminogen activation. Similarly, Lp(a) enhanced (up to 2.5-fold) plasminogen binding to immobilized fibrin in both buffer and plasma milieus at the physiological concentration of plasminogen (2.0 microM). In conclusion, Lp(a) had no effect on plasminogen activation by pro-UK and induced only limited inhibition of activation by t-PA.(ABSTRACT TRUNCATED AT 250 WORDS)
Vascular Research Laboratory, New England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02215.
J N
JN
Liu
P C
PC
Harpel
R
R
Pannell
V
V
Gurewich
D004792:Enzyme Precursors / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D017270:Lipoprotein(a) / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010958:Plasminogen / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D004792:Enzyme Precursors; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D011994:Recombinant Proteins; D005337:Fibrin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator