title: Dysfunction of annexin A2 contributes to hyperglycaemia-induced loss of human endothelial cell surface fibrinolytic activity.
abstract: 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.
authors.affiliation: Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. haibindai@zju.edu.cn
authors.forename: Haibin
authors.initials: H
authors.lastname: Dai
authors.forename: Zhanyang
authors.initials: Z
authors.lastname: Yu
authors.forename: Xiang
authors.initials: X
authors.lastname: Fan
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hajjar
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
mesh_terms: D017306:Annexin A2 / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology*; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D008833:Microcirculation; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D005341:Fibrinolysin; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D011994:Recombinant Proteins; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10