Neutrophils stimulated by apolipoprotein(a) generate fragments that are stronger inhibitors of plasmin formation than apo(a).
Apolipoprotein(a), the plasminogen-like component of lipoprotein(a), is transformed into fragments by polymorphonuclear neutrophils (PMNs) elastase. Since stimulated PMNs express urokinase-type plasminogen activator (uPA), we sought to investigate the relevance of apo(a) fragmentation on plasminogen activation by neutrophils. Freshly isolated human PMNs stimulated by a 10 kringle recombinant apo(a), r-apo(a), activate plasminogen in a specific and saturable manner (Km = 476 +/- 42 nM, Vmax = 896 +/- 18 pmol min(-1)). This activation is prevented by amiloride, an inhibitor of u-PA, and epsilon-aminocaproic acid, epsilon-ACA, a lysine analogue that blocks plasminogen binding to PMNs. Stimulation of PMNs by apo(a) results in the formation of elastase-derived apo(a) fragments. These fragments produce a concentration-dependent decrease in the formation of plasmin. Addition of elastase inhibitors to PMNs prevented degradation of apo(a) and partially restored the formation of plasmin. In a similar manner, isolated r-apo(a) fragments were able to produce a 100% decrease in plasmin generation as compared to intact r-apo(a). These data indicate that apo(a) fragments produce a more pronounced inhibition in the generation of cell-bound plasmin by uPA than the parent apo(a). These effects of apo(a) and its fragments were neutralised by a monoclonal antibody directed against the lysine-binding site of apo(a). This mechanism may be of biological relevance to the effects of Lp(a) in conditions where PMNs accumulate and release elastase, i.e. thrombus lysis and inflammatory lesions.
Lamanuzzi
Leila B
LB
Department of Biochemistry & Molecular Biology & IBBE-CNR, University of Bari, Italy.
Mtairag
El Mostafa
el M
Pepe
Gabriella
G
Anglés-Cano
Eduardo
E
D001054:Apolipoproteins A / Q000378:metabolism*; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007700:Kinetics; D018082:Kringles; D019272:Leukocyte Elastase / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D010958:Plasminogen / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D001054:Apolipoproteins A; D010446:Peptide Fragments; D010958:Plasminogen; D019272:Leukocyte Elastase; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator