Dual effect of apolipoprotein(a) on plasmin(ogen)-induced apoptosis through modulation of cell detachment of adherent cells.
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).
Ho-Tin-Noé
Benoît
B
INSERM U698, Paris 18, France.
Meilhac
Olivier
O
Rossignol
Patrick
P
Lijnen
H Roger
HR
Anglés-Cano
Eduardo
E
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D001667:Binding, Competitive; D016466:CHO Cells; D002448:Cell Adhesion; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000494:pharmacology*; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology
D001054:Apolipoproteins A; D011994:Recombinant Proteins; D010958:Plasminogen; D005341:Fibrinolysin