Aleman Maria M, Holle Lori A, Stember Katherine G, Devette Christa I, Monroe Dougald M, Wolberg Alisa S
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS One. 2015 Apr 27;10(4):e0124448. doi: 10.1371/journal.pone.0124448. eCollection 2015.
Transglutaminases are a superfamily of isoenzymes found in cells and plasma. These enzymes catalyze the formation of ε-N-(γ-glutamyl)-lysyl crosslinks between proteins. Cystamine blocks transglutaminase activity and is used in vitro in human samples and in vivo in mice and rats in studies of coagulation, immune dysfunction, and inflammatory disease. These studies have suggested cystamine blocks fibrin crosslinking and has anti-inflammatory effects, implicating transglutaminase activity in the pathogenesis of several diseases. We measured the effects of cystamine on fibrin crosslinking, tissue factor-triggered plasma clot formation and thrombin generation, and coagulation factor enzymatic activity. At concentrations that blocked fibrin crosslinking, cystamine also inhibited plasma clot formation and reduced thrombin generation. Cystamine inhibited the amidolytic activity of coagulation factor XI and thrombin towards chromogenic substrates. These findings demonstrate that cystamine exhibits anticoagulant activity during coagulation. Given the close relationship between coagulation and inflammation, these findings suggest prior studies that used cystamine to implicate transglutaminase activity in disease pathogenesis warrant re-examination.
转谷氨酰胺酶是一类存在于细胞和血浆中的同工酶超家族。这些酶催化蛋白质之间形成ε-N-(γ-谷氨酰)-赖氨酰交联。胱胺可阻断转谷氨酰胺酶活性，在关于凝血、免疫功能障碍和炎症性疾病的研究中，被用于人体样本的体外实验以及小鼠和大鼠的体内实验。这些研究表明，胱胺可阻断纤维蛋白交联并具有抗炎作用，提示转谷氨酰胺酶活性参与了多种疾病的发病机制。我们测定了胱胺对纤维蛋白交联、组织因子触发的血浆凝块形成和凝血酶生成以及凝血因子酶活性的影响。在阻断纤维蛋白交联的浓度下，胱胺还抑制了血浆凝块形成并减少了凝血酶生成。胱胺抑制了凝血因子XI和凝血酶对发色底物的酰胺水解活性。这些发现表明，胱胺在凝血过程中表现出抗凝活性。鉴于凝血与炎症之间的密切关系，这些发现提示，先前利用胱胺来表明转谷氨酰胺酶活性参与疾病发病机制的研究值得重新审视。
