Nicked beta2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis.
Nicked beta2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis.
复制标题
带缺口的β2-糖蛋白I：脑梗塞的标志物和外源性纤溶负反馈途径中的新作用。
作者：
S. Yasuda;T. Atsumi;M. Ieko;E. Matsuura;Kazuko Kobayashi;J. Inagaki;H. Kato;Hideyuki Tanaka;M. Yamakado;M. Akino;Hisatoshi Saitou;Y. Amasaki;S. Jodo;O. Amengual;T. Koike
BEta（2）-糖蛋白I（β（2）-GPI）在结构域V（切口β（2）-GPI）中被纤溶酶蛋白水解切割，不能与磷脂结合。这种裂解可能发生在体内，在大量纤溶酶生成和纤溶转换的患者中检测到切口β（2）-GPI的血浆水平升高。在这项研究中，我们报告了与磁共振成像正常的健康受试者（8%）相比，缺血性卒中患者（63%）和腔隙性梗死健康受试者（27%）中切口β（2）-GPI与总β（2）-GPI比值升高的患病率更高，提示在血栓形成患者中，缺口β 2-GPI可能具有超出其母体分子的生理作用。几种外源性纤维蛋白溶解抑制剂是已知的，但负反馈调节剂尚未记录。我们证明，缺口β（2）-GPI与Glu-纤溶酶原结合的K（D）为0.37 × 10（-6）M，推测是由缺口β（2）-GPI的第五个结构域与Glu-纤溶酶原的第五个kringle结构域之间的相互作用介导的。在存在组织纤溶酶原激活物、纤溶酶原和纤维蛋白的情况下，缺口β（2）-GPI也抑制纤溶酶生成高达70%。完整的beta（2）-GPI缺乏这些特性。这些数据表明β（2）-GPI/纤溶酶切口的β（2）-GPI通过负反馈途径环控制外源性纤维蛋白溶解。
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.