Nicked  2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis

Abstract

␤ 2 -Glycoprotein I (␤ 2 -GPI) is proteolytically cleaved by plasmin in domain V (nicked ␤ 2 -GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked ␤ 2 -GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked ␤ 2 -GPI against total ␤ 2 -GPI in patients with ischemic stroke (63%) and healthy subjects with lacunar infarct (27%) when compared to healthy subjects with normal findings on magnetic resonance imaging (8%), suggesting that nicked ␤ 2 -GPI might have a physiologic role beyond that of its parent molecule in patients with thrombosis. Several inhibitors of extrinsic fibrinolysis are known, but a negative feedback regulator has not been yet documented. We demonstrate that nicked ␤ 2 -GPI binds to Glu-plasminogen with K D of 0.37 ؋ 10 ؊6 M, presumably mediated by the interaction between the fifth domain of nicked ␤ 2 -GPI and the fifth kringle domain of Glu-plasminogen. Nicked ␤ 2 -GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact ␤ 2 -GPI lacks these properties. These data suggest that ␤ 2 -GPI/plasmin-nicked ␤ 2 -GPI controls extrinsic fibrinolysis via a negative feedback pathway loop. Introduction␤ 2 -Glycoprotein I (␤ 2 -GPI), also known as apolipoprotein H, is a phospholipid-binding plasma protein. Phospholipid-bound ␤ 2 -GPI is one of the major target antigens for antiphospholipid antibodies 1-3 present in patients with antiphospholipid syndrome (APS), an autoimmune disorder characterized by arterial/venous thrombosis and pregnancy morbidity. 4 ␤ 2 -GPI has 5 homologous short consensus repeats, designated as domains I to V. Domains of ␤ 2 -GPI structurally resemble each other, except that domain V has an extra C-terminal loop and a positively charged lysine cluster. In 1993, Hunt et al 5 reported that ␤ 2 -GPI is proteolytically cleaved between Lys317 and Thr318 in domain V (nicked ␤ 2 -GPI), being unable to bind to phospholipids. This cleavage is generated by factor Xa or by plasmin, with plasmin being more effective. 6 A large number of reports have detailed the in vitro properties of ␤ 2 -GPI as a natural anticoagulant/procoagulant regulator by inhibiting phospholipid-dependent reactions, such as prothrombinase and tenase activity on platelets or phospholipid vesicles, 7,8 factor XII activation, 9 and anticoagulant activity of activated protein C. 10,11 Apart from specific hemostatic functions, ␤ 2 -GPI activates lipoprotein lipase, 12 lowers the triglyceride level, 13 binds to oxidized low-density lipoprotein to prevent the progression of atherosclerosis, 14 and binds to nonself particles or apoptotic bodies to allow their clearance. [15][16][17] Little attention has been given to the functions of the nicked form of ␤ 2 -GPI because its phospholipidbinding activity was thought to exert the physiologic or pathologic functions of ␤ 2 -GPI.Fibrinolytic reactions ...

Dietary oil modifies the plasma proteome during aging in the rat

“…On the other hand, anticoagulant properties have also been attributed to this protein interceding in the coagulation cascade (Miyakis et al 2004). Finally, β 2 GPI has also been proposed as a marker of cerebral infarction (Yasuda et al 2004). The decrease of β 2 GPI in animals fed with the VOO diet regardless of age again reinforces the benefits of prolonged consumption of a diet rich in VOO.…”

Domain V of β2-Glycoprotein I Binds Factor XI/XIa and Is Cleaved at Lys317-Thr318

“…Regulation of plasmin generation is important in in vivo fibrinolytic homeostasis. Proteolytically cleaved ␤ 2 GPI at Lys 317 -Thr 318 has recently been demonstrated to inhibit plasmin generation by tissue plasminogen activator (33). The clipped form of ␤ 2 GPI correlated with in vitro markers of fibrinolytic activity.…”

“…The FXIa cleavage of ␤ 2 GPI in this complex would regulate the activation of FXI by thrombin, providing a negative feedback loop in FXI activation. Furthermore, c␤ 2 GPI binds Glu-plasminogen-suppressing plasmin generation, thus providing a negative feedback loop controlling fibrinolysis (33). A schematic representation of the effect of c␤ 2 GPI and intact ␤ 2 GPI on this pathway is shown in Fig.…”

“…However, Koike and co-workers (33) have recently demonstrated that ␤ 2 GPI proteolytically cleaved by plasmin further suppresses plasmin generation by binding to Glu-plasminogen via DV. This interaction suggests a negative feedback loop controlling extrinsic fibrinolysis (33). Increased levels of clipped ␤ 2 GPI (c␤ 2 GPI) have been reported in the plasma of patients with lupus anticoagulant and in patients with disseminated intravascular coagulation (13).…”

Anti-prothrombin antibodies in type 1 diabetes mellitus

“…β2GP1, also known as apolipoprotein H, is an abundant phospholipid-binding protein which circulates in the plasma [16]. Recent studies have demonstrated that β2GP1 may interact directly with the components of the plasminogen activator system and affect the generation of cell surface and plasma fibrinolytic activity [17,18].…”