Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?
High plasma levels of lipoprotein(a) [Lp(a)] are considered to be an independent risk factor for premature cardiovascular disease and are inversely associated with apolipoprotein(a) [apo(a)] isoform sizes. The contribution of apo(a) polymorphism to the inhibition of fibrinolysis, a mechanism that may favor thrombus development, was therefore evaluated by measuring the ability of Lp(a) particles of distinct apo(a) isoform content to compete with plasminogen for fibrin binding during plasminogen activation by fibrin-bound tissue-type plasminogen activator. The rate of plasmin generation was most efficiently inhibited by an isoform with a molecular weight (M(r)) of approximately 540 Kd. An isoform with M(r) approximately 590 Kd produced a less pronounced effect, whereas the isoform with M(r) approximately 610 Kd failed to inhibit plasminogen activation. These effects were directly proportional to the amount of Lp(a) bound to the carboxy-terminal lysine residues of degraded fibrin. The relative affinity of the binding (kd range, 16 to 180 nmol/L) reflected the ability of individual Lp(a) isoforms to inhibit the binding of plasminogen (kd, 600 nmol/L). The question of the influence of kringle sequence variability on the binding to fibrin was not addressed by the present work. These data suggest that apo(a) isoform types with high affinity for fibrin may influence the ability of Lp(a) to interfere with fibrinolysis and contribute thereby to the association of elevated levels of Lp(a) with atherosclerotic and thrombotic risks.
Hervio
L
L
Institut National de la Santé et de la Recherche Médicale, INSERM U. 143, Hôpital de Bicêtre, Paris, France.
Chapman
M J
MJ
Thillet
J
J
Loyau
S
S
Anglés-Cano
E
E
D001054:Apolipoproteins A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D004591:Electrophoresis, Polyacrylamide Gel; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood* / Q000737:chemistry; D010641:Phenotype; D010958:Plasminogen / Q000378:metabolism; D011110:Polymorphism, Genetic; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D001054:Apolipoproteins A; D017270:Lipoprotein(a); D005337:Fibrin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator