Lipoprotein(a) binds to human platelets and attenuates plasminogen binding and activation.
Lipoprotein(a) [Lp(a)] is a unique lipoprotein consisting of a low-density lipoprotein moiety (LDL) covalently linked to apoprotein(a). Previous work has demonstrated that Lp(a) can compete with plasminogen (PGN) for binding to endothelial and mononuclear cells and can inhibit PGN activation in cell-free systems. We have assessed the binding of Lp(a) to platelets and the influence of binding on the activation of PGN by tissue-type plasminogen activator (t-PA) in this system. In direct binding experiments, Lp(a) bound specifically, saturably, and reversibly to platelets with an estimated apparent Kd of 0.20 microM. Scatchard analysis revealed a single class of binding sites with 81,000 +/- 22,000 particles of Lp(a) bound at saturation. Interestingly, Lp(a) bound to a similar extent to thromboasthenic platelets. Activation of platelets with ADP or thrombin reduced Lp(a) binding capacity by approximately 50% without changing affinity. Lp(a) also inhibited the binding of PGN to platelets with an IC50 of approximately 0.23 microM. Over a similar concentration range, LDL did not inhibit PGN binding to platelets. In addition, Lp(a) inhibited PGN binding to plasmin-treated platelets with an IC50 of approximately 0.2 microM. Kinetic experiments demonstrated that Lp(a) acted as a competitive inhibitor of PGN activation by t-PA on the platelet surface, with an estimated Ki of 0.49 microM. In the presence of platelets, Lp(a) decreased the kcat/Km for t-PA by 3-fold, owing primarily to an increase in the Km of t-PA for PGN. In contrast, LDL did not alter the kinetics of PGN activation by t-PA on the platelet surface.(ABSTRACT TRUNCATED AT 250 WORDS)
Ezratty
A
A
Cardiovascular Divisions, Brigham and Women's Hospital, Boston, Massachusetts.
Simon
D I
DI
Loscalzo
J
J
D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism*; D005732:Gangliosides / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D017270:Lipoprotein(a) / Q000097:blood* / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism*; D015539:Platelet Activation; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000494:pharmacology
D005732:Gangliosides; D017270:Lipoprotein(a); D010958:Plasminogen; D010959:Tissue Plasminogen Activator