Nicked beta2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis.
BEta(2)-glycoprotein I (beta(2)-GPI) is proteolytically cleaved by plasmin in domain V (nicked beta(2)-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked beta(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 beta(2)-GPI against total beta(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 beta(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 beta(2)-GPI binds to Glu-plasminogen with K(D) of 0.37 x 10(-6) M, presumably mediated by the interaction between the fifth domain of nicked beta(2)-GPI and the fifth kringle domain of Glu-plasminogen. Nicked beta(2)-GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact beta(2)-GPI lacks these properties. These data suggest that beta(2)-GPI/plasmin-nicked beta(2)-GPI controls extrinsic fibrinolysis via a negative feedback pathway loop.
Yasuda
Shinsuke
S
Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Atsumi
Tatsuya
T
Ieko
Masahiro
M
Matsuura
Eiji
E
Kobayashi
Kazuko
K
Inagaki
Junko
J
Kato
Hisao
H
Tanaka
Hideyuki
H
Yamakado
Minoru
M
Akino
Minoru
M
Saitou
Hisatoshi
H
Amasaki
Yoshiharu
Y
Jodo
Satoshi
S
Amengual
Olga
O
Koike
Takao
T
D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002544:Cerebral Infarction / Q000097:blood / Q000209:etiology*; D025461:Feedback, Physiological; D005260:Female; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D005342:Fibrinolysis; D006023:Glycoproteins / Q000097:blood / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D013927:Thrombosis / Q000097:blood / Q000209:etiology; D053482:beta 2-Glycoprotein I
D015415:Biomarkers; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I; D010958:Plasminogen; D005341:Fibrinolysin