Dual effect of apolipoprotein(a) on plasmin(ogen)-induced apoptosis through modulation of cell detachment of adherent cells

Benoît Ho-Tin-Noé; Olivier Meilhac; Patrick Rossignol; H. Roger Lijnen; Eduardo Anglés-Cano

doi:10.1160/TH05-07-0505

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(01): 142-150
DOI: 10.1160/TH05-07-0505

Cellular Proteolysis and Oncology

Schattauer GmbH

Dual effect of apolipoprotein(a) on plasmin(ogen)-induced apoptosis through modulation of cell detachment of adherent cells

Authors

Benoît Ho-Tin-Noé

¹INSERM U698, Paris, France

²Université Paris Denis Diderot, Paris, France
Olivier Meilhac

¹INSERM U698, Paris, France

²Université Paris Denis Diderot, Paris, France
Patrick Rossignol

¹INSERM U698, Paris, France

²Université Paris Denis Diderot, Paris, France
H. Roger Lijnen

³Center for Molecular and Vascular Biology, Katholieke Universitet Leuven, Belgium
Eduardo Anglés-Cano

¹INSERM U698, Paris, France

²Université Paris Denis Diderot, Paris, France

Abstract

Summary

Because of its structural homology with plasminogen, the apolipoprotein(a) [apo(a)] component of the athero-thrombogenic lipoprotein(a) [Lp(a)] particle inhibits plasminogen binding and activation onto fibrin as well as the subsequent fibrinolysis. In a similar manner, apo(a) may also interfere with plasmin(ogen)-induced cell detachment and apoptosis of adherent cells. To investigate this hypothesis, we studied the effect of a recombinant apo(a) [r-apo(a)] on plasminogen activation-induced apoptosis of vascular smooth muscle cells (VSMCs) and fibroblasts-like CHO-K1 cells. We demonstrate for the first time that apo(a) displays a concentration-dependent biphasic, enhancing/preventing effect on plasmin(ogen) induced cell detachment of VSMCs and CHO-K1 cells. Our results show that r-apo(a) binds to these cells with higher affinity than plasminogen [Kd = 0.9 ± 0.2 µM for plasminogen, Kd = 1.77 ± 0.34 nM for r-apo(a)] in a lysine-dependent manner. At high r-apo(a)/plasminogen ratios, their competitive interaction results in a partial inhibition of plasminogen activation by cell-bound t-PA. As a consequence, r-apo(a) prevents plasmin(ogen)-induced cell detachment and apoptosis. Surprisingly,at low r-apo(a)/plasminogen ratios,an enhancement in plasmin(ogen)-induced cell detachment and apoptosis was observed. This effect was shown to be “plasmin-selective” as r-apo(a) was unable to potentiate cell detachment induced by human neutrophil elastase and trypsin. Altogether these data are consistent with a new mechanism of apo(a)/plasmin(ogen) interactions that may contribute to the atherothrombogenic potential of Lp(a).

Keywords

Apolipoprotein(a) - cell detachment-induced apoptosis - plasminogen - vascular smooth muscle cells - CHO-K1 cells

Full Text

References

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