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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2036-2043.)
© 1997 American Heart Association, Inc.

Articles

Lipoprotein(a) Isoforms Display Differences in Affinity for Plasminogen-Like Binding to Human Mononuclear Cells

C. Kang; V. Durlach; T. Soulat; C. Fournier; ; E. Anglés-Cano

From INSERM U.143 (C.K., T.S., E.A-C.) and the Cardiology Department (C.F.), Hôpital de Bicêtre, Paris, and Clinique Médicale of the CHUR de Reims (V.D.), France.

Correspondence to Dr. E. Anglés-Cano, INSERM U.143, Hôpital de Bicêtre, Bât. C. Bernard, F-94276-Cedex, Bicêtre, France. E mail angles@infobiogen.fr or angles@kb.inserm.fr

Abstract Binding of lipoprotein(a) (Lp(a)) to membrane proteins of the monocyte-macrophage cell lineage may be an important event in atheroma formation. Since Lp(a) with distinct apolipoprotein(a) (apo(a)) isoforms may show differences in their affinity with regard to fibrin binding, the existence of such a functional behavior in the interaction of apo(a) in Lp(a) with these cells was explored using the monocytic cell line THP-1. Lp(a) preparations containing small size apo(a) isoforms (M_r=450 000 to 550 000) and high molecular mass isoforms (M_r700 000) were purified from plasmas containing >0.35 g/L of Lp(a) obtained from subjects (n=14) with cardiovascular atherosclerotic disease. Binding of plasminogen to THP-1 cells was performed using the method of radioisotopic dilution. For binding of Lp(a) to cells, the THP-1 monocytic cells were incubated with varying concentrations of the different Lp(a) preparations; cells were then washed and the amount of Lp(a) bound was detected with a radiolabeled polyclonal antibody directed against apo(a). Binding due to kringle interactions with lysine residues was calculated by subtracting from the total bound the amount of Lp(a) bound (10%) in the presence of 6-aminohexanoic acid. Analysis of data with the Langmuir equation indicated identical and independent (noninteracting) sites and allowed evaluation of the K_d. Binding isotherms of small size isoforms showed saturation and a high affinity (K_d=25.8±19 nmol/L) relative to that of plasminogen (K_d=1750±760 nmol/L). A similar difference (K_d=17.5±7.9 nmol/L versus K_d=600±220 nmol/L) was found when binding experiments were performed with a fibrin surface. In contrast, binding isotherms of the high molecular mass isoforms did not show saturation at the highest Lp(a) concentrations used, thus indicating a lower affinity. In conclusion, these results show that apo(a) isoforms may display polymorphism-linked functional heterogeneity with regard to cell binding, which may explain the higher association with cardiovascular risk of small size isoforms. These qualitative differences in the binding of apo(a) isoforms to fibrin or cells may modulate the cardiovascular risk associated with high levels of Lp(a).

Key Words: lipoprotein(a) • apo(a) isoforms • plasminogen • monocytes

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