Dysfunction of annexin A2 contributes to hyperglycaemia-induced loss of human endothelial cell surface fibrinolytic activity.
Dysfunction of annexin A2 contributes to hyperglycaemia-induced loss of human endothelial cell surface fibrinolytic activity.
复制标题
膜联蛋白 A2 功能障碍导致高血糖诱导的人内皮细胞表面纤溶活性丧失
DOI：
10.1160/th12-12-0944
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发表时间：
2013-06
影响因子：
6.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Dai H;Yu Z;Fan X;Liu N;Yan M;Chen Z;Lo EH;Hajjar KA;Wang X
高脂血症损害内皮细胞表面的纤溶活性，但其潜在机制尚未完全清楚。在这项研究中，我们测试的假设，即高血糖症导致内皮细胞膜蛋白膜联蛋白A2功能障碍，从而导致整体降低纤溶活性。高脂血症7天显著降低人脑微血管内皮细胞（HBMEC）细胞表面纤溶活性。高脂血症还降低了组织型纤溶酶原激活物（t-PA）、纤溶酶原和膜联蛋白A2的mRNA和蛋白表达，同时增加了纤溶酶原激活物抑制物-1（派-1）。未检测到p11 mRNA或蛋白表达的变化。高脂血症显着增加总细胞和膜联蛋白A2的AGE修饰形式。与重组膜联蛋白A2（rA 2）孵育后，高血糖相关的纤溶活性降低完全恢复，但不是AGE修饰的膜联蛋白A2或外源性t-PA。高脂血症降低t-PA，上调派-1，并诱导AGE相关的膜联蛋白A2功能的破坏，所有这些都有助于内皮细胞表面纤溶活性的整体降低。进一步研究以阐明A2衍生化的潜在分子机制和病理生理学意义，最终可能会更好地了解血管纤维蛋白溶解受损的机制，并开发针对糖尿病血栓性血管并发症的新干预策略。
Summary Hyperglycaemia impairs fibrinolytic activity on the surface of endothelial cells, but the underlying mechanisms are not fully understood. In this study, we tested the hypothesis that hyperglycaemia causes dysfunction of the endothelial membrane protein annexin A2, thereby leading to an overall reduction of fibrinolytic activity. Hyperglycaemia for 7 days significantly reduced cell surface fibrinolytic activity in human brain microvascular endothelial cells (HBMEC). Hyperglycaemia also decreased tissue type plasminogen activator (t-PA), plasminogen, and annexin A2 mRNA and protein expression, while increasing plasminogen activator inhibitor-1 (PAI-1). No changes in p11 mRNA or protein expression were detected. Hyperglycaemia significantly increased AGE-modified forms of total cellular and membrane annexin A2. The hyperglycemia-associated reduction in fibrinolytic activity was fully restored upon incubation with recombinant annexin A2 (rA2), but not AGE-modified annexin A2 or exogenous t-PA. Hyperglycaemia decreased t-PA, upregulated PAI-1 and induced AGE-related disruption of annexin A2 function, all of which contributed to the overall reduction in endothelial cell surface fibrinolytic activity. Further investigations to elucidate the underlying molecular mechanisms and pathophysiological implications of A2 derivatisation might ultimately lead to a better understanding of mechanisms of impaired vascular fibrinolysis, and to development of new interventional strategies for the thrombotic vascular complications in diabetes.