Comparison of the effects of apo(a) kringle IV-10 and plasminogen kringleson the interactions of lipoprotein(a) with regulatory molecules

Lipoprotein(a) [Lp(a)] is associated with atherosclerosis and with disease processes involving thrombosis. Lp(a) contains apoprotein (a) [apo(a)], whi ch has a sequence highly homologous to plasminogen. Hence, Lp(a) binds dire ctly to extracellular matrix, cellular plasminogen receptors and fibrin(oge n) and competes for the binding of plasminogen to these regulatory surfaces . These interactions may contribute to the proatherothrombogenic consequenc es of high Lp(a) levels. These interactions are mediated by lysine binding sites (LBS). Therefore, we examined the role of apo(a) kringle IV-10 [the o nly apo(a) kringle demonstrated to exhibit lysine binding activity in the i ntact lipoprotein] in the interaction of Lp(a) with these regulatory molecu les. We have compared directly apo(a) KIV-10 with plasminogen K4 to examine whether these highly structurally homologous kringle modules are also func tionally homologous. Futhermore, because the plasminogen K5-protease (K5-PD ) binds directly to fibrin, we have also examined the ability of this plasm inogen fragment to inhibit the interaction of Lp(a) with these regulatory m olecules and with extracellular matrix. Apo(a) KIV-10 competed effectively for the binding of I-125-Lp(a) to these surfaces but was less effective tha n either intact Lp(a), plasminogen K4 or plasminogen. Plasminogen KS-PD was a better competitor than apo(a) KIV-10 for I-125-Lp(a) binding to the repr esentative extracellular matrix, Matrigel, and to plasmin-treated fibrinoge n. In contrast, plasminogen KS-PD did not compete for the interaction of Lp (a) with cells, although it effectively competed for plasminogen binding. T hese results suggest that Lp(a) recognizes sites in all of the regulatory m olecules that are also recognized by apo(a) KIV-10 and that Lp(a) recognize s sites in extracellular matrix and in plasmin-modified fibrinogen that als o are recognized by plasminogen KS-PD. Thus, the interaction of Lp(a) with cells is clearly distinct from that with extracellular matrix and with plas min-treated fibrinogen and the recognition sites within Lp(a) and plasminog en for these regulatory molecules are not identical.