The role of β2-glycoprotein I (β 2 GPI) in the activation of plasminogen Francisco López-Lira a,b , Luis Rosales-León a , Verónica Monroy Martínez a , Blanca H. Ruiz Ordaz a, ⁎ a Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, UNAM, Ciudad Universitaria 04510, México, D.F., Mexico b Laboratorio de Inmunología, Instituto Nacional de Pediatría, SSA, México, D.F., Mexico Received 9 November 2005; received in revised form 21 December 2005; accepted 22 December 2005 Available online 19 January 2006 Abstract β2-glycoprotein I (β 2 GPI) is a glycoprotein of unknown physiological function. It is the main target antigen for antiphospholipid antibodies in patients with antiphospholipid syndrome (APS). β 2 GPI binds with high affinity to the atherogenic lipoprotein Lp(a) which shares structural homology with plasminogen, a key molecule in the fibrinolytic system. Impaired fibrinolysis has been described in APS. The present work reports the interaction between β 2 GPI and Glu-Plasminogen which may explain the recently described proteolytic effect of plasmin on β 2 GPI. In the process of Glu-Plasminogen activation, we found an increase in plasmin generation both at fibrin and cellular surface level as a function of the concentration of β 2 GPI added, suggesting an important role as a cofactor in the trimolecular complex β 2 GPI-Plasminogen-tPA. This phenomenon represents a novel regulatory step both in the positive feedback mechanism for extrinsic fibrinolysis and in antithrombotic regulation. IgG anti- β 2 GPI antibodies recognized the β 2 GPI at the endothelial surface inducing its activation with an increase of ICAM-I and a decrease in the expression of thrombomodulin favoring a pro-thrombotic state in the vascular endothelium. The interference in the plasmin conversion by anti- β 2 GPI antibodies could generate thrombosis as observed in APS. © 2005 Elsevier B.V. All rights reserved. Keywords: β2-glycoprotein; Plasmin; Plasminogen activation; Fibrinolysis; Thrombosis 1. Introduction Beta-2-glycoprotein I (β 2 GPI), also known as apolipoprotein H, is an abundant human plasma glycoprotein that is found in both free and lipoprotein-associated forms [1]. It is a single chain protein that consists of 326 amino acids and has a molecular mass of 42 kDa. β 2 GPI is composed of five contiguous domains, four of which are highly homologous and contain ∼60 amino acid residues and two disulfide bonds. The fifth domain is aberrant since it contains ∼80 amino acids, an extra C-terminal loop and a positively-charged lysine cluster, in particular the regions Cys281 to Cys288 and Ser311 to Lys317 [2]. β 2 GPI has high affinity for negatively charged phospholipids and has been identified as the primary target antigen recognized by circulating autoantibodies in patients with antiphospholipid syndrome (APS), which is clinically characterized by recurrent venous and arterial thrombosis, miscarriages and thrombocytopenia [3,4]. Different studies have shown that there is a significant correlation between thrombotic manifestations and the presence of anti-β 2 GPI antibodies in these patients [4,5]. However, β 2 GPI has both negative and positive effects on coagulation in vitro since it can inhibit the contact activation pathway of coagulation [6], and the anticoagulant effect of activated protein C [7]. Although the physiological function(s) of β 2 GPI in biolog- ical fluids is unknown, a role in lipid metabolism has been sug- gested by the observations that 30% of plasma β 2 GPI circulates complexed to lipoproteins [1,8] and that β 2 GPI accelerates tri- glyceride clearance in rat [9]. β 2 GPI also binds with high affinity to the atherogenic lipoprotein Lp(a) by the kringle 4 domains of apo(a) in a specific manner [10]. Apolipoprotein(a) shares ex- tensive sequence homology with plasminogen [11], which is the inactive precursor of the protease plasmin and plays a key role in the blood clot dissolution [12]. Native plasminogen is a single- chain polypeptide of 791 amino acids consisting of an amino- terminal glutamic acid followed by a tandem of five homologous triple-loop structures called kringle domains and a carboxy- terminal serine protease domain. Plasminogen binds to fibrin, Biochimica et Biophysica Acta 1764 (2006) 815 – 823 http://www.elsevier.com/locate/bba ⁎ Corresponding author. E-mail address: bhro@servidor.unam.mx (B.H. Ruiz Ordaz). 1570-9639/$ - see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.bbapap.2005.12.020