Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein(a)-mediated inhibition of plasminogen activation.
BACKGROUND
Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with an increased risk for thrombotic disorders. Lp(a) is a unique lipoprotein consisting of a low-density lipoprotein-like moiety covalently linked to apolipoprotein(a) [apo(a)], a homologue of the fibrinolytic proenzyme plasminogen. Several in vitro and in vivo studies have shown that Lp(a)/apo(a) can inhibit tissue-type plasminogen activator-mediated plasminogen activation on fibrin surfaces, although the mechanism of inhibition by apo(a) remains controversial. Essential to fibrin clot lysis are a number of plasmin-dependent positive feedback reactions that enhance the efficiency of plasminogen activation, including the plasmin-mediated conversion of Glu-plasminogen to Lys-plasminogen.


OBJECTIVE
Using acid-urea gel electrophoresis to resolve the two forms of radiolabeled plasminogen, we determined whether apo(a) is able to inhibit Glu-plasminogen to Lys-plasminogen conversion.


METHODS
The assays were performed in the absence or presence of different recombinant apo(a) species, including point mutants, deletion mutants and variants that represent greater than 90% of the known apo(a) isoform sizes.


RESULTS
Apo(a) substantially suppressed Glu-plasminogen conversion. Critical roles were identified for the kringle IV types 5-9 and kringle V; contributory roles for sequences within the amino-terminal half of the molecule were also observed. Additionally, with the exception of the smallest naturally-occurring isoform of apo(a), isoform size was found not to contribute to the inhibitory capacity of apo(a).


CONCLUSIONS
These findings underscore a novel contribution to the understanding of Lp(a)/apo(a)-mediated inhibition of plasminogen activation: the ability of the apo(a) component of Lp(a) to inhibit the key positive feedback step of plasmin-mediated Glu-plasminogen to Lys-plasminogen conversion.
Feric
N T
NT
Department of Biochemistry, Queen's University, Kingston, ON, Canada.
Boffa
M B
MB
Johnston
S M
SM
Koschinsky
M L
ML
D001054:Apolipoproteins A / Q000494:pharmacology*; D002460:Cell Line; D005337:Fibrin; D005342:Fibrinolysis; D006801:Humans; D007668:Kidney / Q000166:cytology; D018082:Kringles; D010446:Peptide Fragments / Q000378:metabolism*; D010958:Plasminogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010959:Tissue Plasminogen Activator
D001054:Apolipoproteins A; D010446:Peptide Fragments; C018998:lysyl-plasminogen; D005337:Fibrin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator