Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems.
Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems.
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DOI：
10.1016/j.jtha.2022.12.015
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发表时间：
2023-04
影响因子：
10.4
通讯作者：
Philippou, Helen
中科院分区：
文献类型：
--
作者：
Hardy, Lewis J.;Bohinc, Dillon;Bane, Kara L.;Heal, Samantha L.;Hethershaw, Emma;Ali, Majid;Palmer-Dench, Thomas;Foster, Richard;Longstaff, Colin;Renne, Thomas;Stavrou, Evi X.;Philippou, Helen
关键词：
人血清白蛋白（HSA）是体内最丰富的血浆蛋白，对糖基化敏感。糖尿病（DM）患者的慢性高血糖状态诱导非酶促美拉德反应，使血浆蛋白变性并形成晚期糖基化终产物（AGEs）。HSA-AGE是糖尿病患者中普遍存在的错误折叠蛋白，与因子XII激活和下游促炎钾likrein-激肽系统活性相关，而与内在途径的促凝活性无关。本研究旨在确定HSA-AGE与糖尿病病理生理的相关性。采用免疫印迹法检测糖尿病患者和血糖正常志愿者血浆中FXII、前钾likrein （PK）和裂解的高分子量激肽原的活化情况。本构血浆钾激肽活性通过显色法测定。通过显色试验、血浆凝血试验和全血体外流动模型，探讨了体外生成的HSA-AGE对FXII、PK、FXI、FIX和FX的激活和动力学调节。从糖尿病患者获得的血浆中含有增加的血浆AGEs，激活的FXIIa，并产生裂解的高分子量激肽原。高组成血浆钾激肽酶活性被确定，这与糖化血红蛋白水平正相关，代表了这一现象的第一个证据。体外生成的HSA-AGE触发fxiia依赖性的PK激活，但通过抑制血浆中FXIa和fixa依赖性的FX激活，限制了内在凝血途径的激活。这些数据表明，HSA-AGEs通过FXII和钾likrein-kinin系统激活在DM的病理生理中具有促炎作用。通过HSA-AGEs抑制FXIa和fixa依赖性FX的激活，FXII激活的促凝作用丧失。
Human serum albumin (HSA) is the most abundant plasma protein and is sensitive to glycation in vivo. The chronic hyperglycemic conditions in patients with diabetes mellitus (DM) induce a nonenzymatic Maillard reaction that denatures plasma proteins and forms advanced glycation end products (AGEs). HSA-AGE is a prevalent misfolded protein in patients with DM and is associated with factor XII activation and downstream proinflammatory kallikrein-kinin system activity without any associated procoagulant activity of the intrinsic pathway. This study aimed to determine the relevance of HSA-AGE toward diabetic pathophysiology. The plasma obtained from patients with DM and euglycemic volunteers was probed for activation of FXII, prekallikrein (PK), and cleaved high-molecular-weight kininogen by immunoblotting. Constitutive plasma kallikrein activity was determined via chromogenic assay. Activation and kinetic modulation of FXII, PK, FXI, FIX, and FX via in vitro–generated HSA-AGE were explored using chromogenic assays, plasma-clotting assays, and an in vitro flow model using whole blood. Plasma obtained from patients with DM contained increased plasma AGEs, activated FXIIa, and resultant cleaved cleaved high-molecular-weight kininogen. Elevated constitutive plasma kallikrein enzymatic activity was identified, which positively correlated with glycated hemoglobin levels, representing the first evidence of this phenomenon. HSA-AGE, generated in vitro, triggered FXIIa-dependent PK activation but limited the intrinsic coagulation pathway activation by inhibiting FXIa and FIXa-dependent FX activation in plasma. These data indicate a proinflammatory role of HSA-AGEs in the pathophysiology of DM via FXII and kallikrein-kinin system activation. A procoagulant effect of FXII activation was lost through the inhibition of FXIa and FIXa-dependent FX activation by HSA-AGEs.
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影响因子：
4.8
作者：
Bouma, B;Kroon-Batenburg, LMJ;Gebbink, MFBG
通讯作者：
Gebbink, MFBG
影响因子：
20.3
作者：
Ajjan, Ramzi A.;Gamlen, Toby;Grant, Peter J.
通讯作者：
Grant, Peter J.
影响因子：
2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
HORIUCHI, S
影响因子：
8.2
作者：
Dunn, EJ;Philippou, H;Grant, PJ
通讯作者：
Grant, PJ