Lipoprotein(a): A kinetic study of its influence on fibrin-dependent plasminogen activation by prourokinase or tissue plasminogen activator

Abstract

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)

Demonstration of Covalent Binding of Lipoprotein(a) [Lp(a)] to Fibrin and Endothelial Cells

“…However, this inhibition was of the uncompetitive type (16,(21)(22), which is inconsistent with the hypothetical mechanism of a competition between plasminogen and Lp(a) for lysine residues in fibrin. In transgenic mice expressing the human apo(a) gene, t-PA-induced lysis of human platelet-rich plasma clots was found to be depressed (23).…”

The Solution Phase Interaction between Apolipoprotein(a) and Plasminogen Inhibits the Binding of Plasminogen to a Plasmin-Modified Fibrinogen Surface

“…Consistent with this hypothesis, Lp(a) has been found to compete with plasminogen for binding to fibrin (16-18, 42, 43), endothelial and mononuclear cells (44,45), and platelets (46). Furthermore, Lp-(a) has been shown to inhibit plasminogen activation by tPA on platelets (46) and in the presence of CNBr fibrinogen fragments (23) or D-dimer (24). Clots introduced into the lungs of mice overexpressing apo(a) from a transgene exhibit retarded clot lysis initiated by the infusion of pharmacological doses of tPA (21).…”

“…However, the nature of this inhibitory effect is unclear at present as both competitive (22) and uncompetitive (17,23) mechanisms have been reported. There is also a report that Lp(a) may enhance fibrin clot lysis in Vitro by promoting the binding of plasminogen to fibrin, thereby resulting in enhanced plasminogen activation in the presence of high concentrations of both D-dimer and tPA (24).…”

Perspectives of data analysis of enzyme inhibition and activation, part 4: Equations for calculation of constants of enzyme activation and inhibition

“…not taking into account a course of change of the second V parameter of this biparametrical reaction [9][10][11][12][13][14][15][16][17][18][19][20].…”