Lp(a) particles mold fibrin-binding properties of apo(a) in size-dependent manner: a study with different-length recombinant apo(a), native Lp(a), and monoclonal antibody.
OBJECTIVE
Small-sized apolipoprotein(a) [apo(a)] isoforms with high antifibrinolytic activity are frequently found in cardiovascular diseases, suggesting a role for apo(a) size in atherothrombosis. To test this hypothesis, we sought to characterize the lysine (fibrin)-binding function of isolated apo(a) of variable sizes.


RESULTS
Recombinant apo(a) [r-apo(a)] preparations consisting of 10 to 34 kringles and a monoclonal antibody that neutralizes the lysine-binding function were produced and used in parallel with lipoprotein(a) [Lp(a)] particles isolated from plasma in fibrin-binding studies. All r-apo(a) preparations displayed similar affinity and specificity for lysine residues on fibrin regardless of size (K(d) 3.6+/-0.3 nmol/L) and inhibited the binding of plasminogen with a similar intensity (IC50 16.8+/-5.4 nmol/L). In contrast, native Lp(a) particles displayed fibrin affinities that were in inverse relationship with the apo(a) kringle number. Thus, a 15-kringle apo(a) separated from Lp(a) and a 34-kringle r-apo(a) displayed an affinity for fibrin that was higher than that in the corresponding particles (K(d) 2.5 versus 10.5 nmol/L and K(d) 3.8 versus 541 nmol/L, respectively). However, fibrin-binding specificity of the r-apo(a) preparations and the Lp(a) particles was efficiently neutralized (IC50 0.07 and 4 nmol/L) by a monoclonal antibody directed against the lysine-binding function of kringle IV-10.


CONCLUSIONS
Our data indicate that fibrin binding is an intrinsic property of apo(a) modulated by the composite structure of the Lp(a) particle.
Kang
Chantal
C
INSERM U460, Faculté de Médecine Xavier Bichat, Paris, France.
Dominguez
Miguel
M
Loyau
Stéphane
S
Miyata
Toshiyuki
T
Durlach
Vincent
V
Anglés-Cano
Edouard
E
D000911:Antibodies, Monoclonal / Q000378:metabolism*; D001053:Apolipoproteins / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D001054:Apolipoproteins A / Q000097:blood / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D053241:Apoprotein(a); D001666:Binding Sites, Antibody / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D018082:Kringles / Q000276:immunology; D017270:Lipoprotein(a) / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D008970:Molecular Weight; D010958:Plasminogen / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D001053:Apolipoproteins; D001054:Apolipoproteins A; D017270:Lipoprotein(a); D020033:Protein Isoforms; D011994:Recombinant Proteins; D005337:Fibrin; D010958:Plasminogen; D053241:Apoprotein(a)