Mechanism for the homocysteine-enhanced antifibrinolytic potential of lipoprotein(a) in human plasma.
Lipoprotein(a) and total plasma homocysteine levels are now established as independent atherothrombogenic risk factors. A distinctive pathophysiological feature of lipoprotein(a) is its antifibrinolytic activity, an effect dependent on plasma concentration and high affinity for fibrin of its small size apo(a) component. A stimulating effect of homocysteine on purified lipoprotein(a) has been proposed. However, little is known about their specific interactions in human plasma. We demonstrate by immunochemical, ligand-binding and plasminogen activation studies, that homocysteine modifies the structure and function of lipoprotein(a) in human plasma; it reduces the apo(a)/apoB disulfide bond causing the appearance of free apo(a) with high affinity for fibrin that inhibits plasminogen binding and plasmin formation (r= -0.995, p =0.002). These effects were evident particularly in plasma samples containing lipoprotein(a) with low affinity for fibrin and more than 22 kringles apo(a) isoforms. In contrast, for plasmas containing high fibrin affinity lipoprotein(a) (less than 22 kringles apo[a] isoforms) no significant change neither in fibrin binding nor in plasmin formation was observed. Furthermore, isolated apo(a) recombinants (10 to 34 kringles) that have been shown to display size-independent high affinity for fibrin were not affected by homocysteine, thus confirming lipoprotein(a) as its main target. These results suggest that the pro-atherogenic role already conferred to lipoprotein(a) by small apo(a) isoforms may be extended to large apo(a) isoforms if released in plasma by homocysteine, as this mechanism reveals their high fibrin affinity. Lipoprotein(a) and homocysteine may therefore constitute, if acting in concert, a new risk factor for athero-thrombotic vascular disease.
Nardulli
Marina
M
INSERM U698, CHU Bichat-Claude Bernard, 46 rue Henri Huchard, F-75877-Cdx, Paris 18, France.
Durlach
Vincent
V
Pepe
Gabriella
G
Anglés-Cano
Eduardo
E
D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D004220:Disulfides; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000737:chemistry; D005340:Fibrinogen / Q000737:chemistry; D005342:Fibrinolysis; D006710:Homocysteine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D017270:Lipoprotein(a) / Q000097:blood* / Q000737:chemistry*; D010641:Phenotype; D010958:Plasminogen / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D012307:Risk Factors; D013329:Structure-Activity Relationship; D014162:Transfection
D000933:Antifibrinolytic Agents; D004220:Disulfides; D008024:Ligands; D017270:Lipoprotein(a); D020033:Protein Isoforms; D011994:Recombinant Proteins; D006710:Homocysteine; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen