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  • Title: Dual effect of apolipoprotein(a) on plasmin(ogen)-induced apoptosis through modulation of cell detachment of adherent cells.
    Author: Ho-Tin-Noé B, Meilhac O, Rossignol P, Lijnen HR, Anglés-Cano E.
    Journal: Thromb Haemost; 2006 Jan; 95(1):142-50. PubMed ID: 16543973.
    Abstract:
    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 [K(d) = 0.9 +/- 0.2 microM for plasminogen, K(d) = 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 athero-thrombogenic potential of Lp(a).
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