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Thromb Haemost 2013; 109(06): 1070-1078
DOI: 10.1160/TH12-12-0944
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Dysfunction of annexin A2 contributes to hyperglycaemia-induced loss of human endothelial cell surface fibrinolytic activity

Haibin Dai
1   The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
2   Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Massachussetts, USA
,
Zhanyang Yu
2   Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Massachussetts, USA
,
Xiang Fan
2   Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Massachussetts, USA
,
Ning Liu
2   Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Massachussetts, USA
,
Min Yan
1   The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Zhong Chen
1   The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Eng H. Lo
2   Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Massachussetts, USA
,
Katherine A. Hajjar
3   Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA
,
Xiaoying Wang
2   Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Massachussetts, USA
› Author Affiliations
Further Information

Publication History

Received: 28 December 2012

Accepted after minor revision: 05 March 2013

Publication Date:
22 November 2017 (online)

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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.

Keywords

Annexin A2 - hyperglycaemia - fibrinolytic activity - advanced glycation end-product - human brain microvascular endothelial cells
 

  • References

  • 1 Haratz S, Tanne D. Diabetes, hyperglycaemia and the management of cerebrovascular disease. Curr Opin Neurol 2011; 24: 81-88.
    CrossrefPubMedGoogle Scholar
  • 2 Hess K, Grant PJ. Inflammation and thrombosis in diabetes. Thromb Haemost 2011; 105 (Suppl. 01) S43-S54.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Tjarnlund-Wolf A, Brogren H, Lo EH. et al. Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases. Stroke 2012; 43: 2833-2839.
    CrossrefPubMedGoogle Scholar
  • 4 Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des 2005; 11: 2279-2299.
    CrossrefPubMedGoogle Scholar
  • 5 Hajjar KA. The endothelial cell tissue plasminogen activator receptor. Specific interaction with plasminogen. J Biol Chem 1991; 266: 21962-21970.
    PubMedGoogle Scholar
  • 6 Flood EC, Hajjar KA. The annexin A2 system and vascular homeostasis. Vascul Pharmacol 2011; 54: 59-67.
    CrossrefPubMedGoogle Scholar
  • 7 Ishii H, Yoshida M, Hiraoka M. et al. Recombinant annexin II modulates impaired fibrinolytic activity in vitro and in rat carotid artery. Circ Res 2001; 89: 1240-1245.
    CrossrefPubMedGoogle Scholar
  • 8 Ishii H, Yoshida M, Hajjar KA. et al. Potential role of recombinant annexin II in diabetic vascular injury. Ann N Y Acad Sci 2001; 947: 308-311.
    PubMedGoogle Scholar
  • 9 Zhu H, Fan X, Yu Z. et al. Annexin A2 combined with low-dose tPA improves thrombolytic therapy in a rat model of focal embolic stroke. J Cereb Blood Flow Metab 2010; 30: 1137-1146.
    CrossrefPubMedGoogle Scholar
  • 10 Fan X, Yu Z, Liu J. et al. Annexin A2: a tissue plasminogen activator amplifier for thrombolytic stroke therapy. Stroke 2010; 41: S54-S58.
    CrossrefPubMedGoogle Scholar
  • 11 Walvick RP, Bratane BT, Henninger N. et al. Visualisation of clot lysis in a rat embolic stroke model: application to comparative lytic efficacy. Stroke 2011; 42: 1110-1115.
    CrossrefPubMedGoogle Scholar
  • 12 Ghitescu LD, Gugliucci A, Dumas F. Actin and annexins I and II are among the main endothelial plasmalemma-associated proteins forming early glucose adducts in experimental diabetes. Diabetes 2001; 50: 1666-1674.
    CrossrefPubMedGoogle Scholar
  • 13 Yamagishi S, Nakamura K, Matsui T. et al. Inhibitors of advanced glycation end products (AGEs): potential utility for the treatment of cardiovascular disease. Cardiovasc Ther 2008; 26: 50-58.
    PubMedGoogle Scholar
  • 14 Barlovic DP, Soro-Paavonen A, Jandeleit-Dahm KA. RAGE biology, atherosclerosis and diabetes. Clin Sci 2011; 121: 43-55.
    CrossrefPubMedGoogle Scholar
  • 15 Gugliucci A, Ghitescu L. Is diabetic hypercoagulability an acquired annexinopathy? Glycation of annexin II as a putative mechanism for impaired fibrinolysis in diabetic patients. Med Hypotheses 2002; 59: 247-251.
    CrossrefPubMedGoogle Scholar
  • 16 Wang X, Lee SR, Arai K. et al. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 2003; 09: 1313-1317.
    CrossrefPubMedGoogle Scholar
  • 17 Nagai R, Matsumoto K, Ling X. et al. Glycolaldehyde, a reactive intermediate for advanced glycation end products, plays an important role in the generation of an active ligand for the macrophage scavenger receptor. Diabetes 2000; 49: 1714-1723.
    CrossrefPubMedGoogle Scholar
  • 18 Diaz VM, Hurtado M, Thomson TM. et al. Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro. Gut 2004; 53: 993-1000.
    CrossrefPubMedGoogle Scholar
  • 19 Choi YG, Lim S. Characterisation of anti-advanced glycation end product antibodies to nonenzymatically lysine-derived and arginine-derived glycated products. J Immunoassay Immunochem 2009; 30: 386-399.
    CrossrefPubMedGoogle Scholar
  • 20 Hajjar KA, Gavish D, Breslow JL. et al. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989; 339: 303-305.
    CrossrefPubMedGoogle Scholar
  • 21 Hajjar KA, Acharya SS. Annexin II and regulation of cell surface fibrinolysis. Ann NY Acad Sci 2000; 902: 265-271.
    PubMedGoogle Scholar
  • 22 Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis Res 2010; 07: 260-273.
    CrossrefPubMedGoogle Scholar
  • 23 Juhan-Vague I, Collen D. On the role of coagulation and fibrinolysis in atherosclerosis. Ann Epidemiol 1992; 02: 427-438.
    CrossrefPubMedGoogle Scholar
  • 24 Zorio E, Gilabert-Estelles J, Espana F. et al. Fibrinolysis: the key to new pathogenetic mechanisms. Curr Med Chem 2008; 15: 923-929.
    CrossrefPubMedGoogle Scholar
  • 25 Alessi MC, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008; 99: 995-1000.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Shen GX. Vascular cell-derived fibrinolytic regulators and atherothrombotic vascular disorders. Int J Mol Med 1998; 01: 399-408.
    PubMedGoogle Scholar
  • 27 Robbie LA, Booth NA, Brown AJ. et al. Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler Thromb Vasc Biol 1996; 16: 539-545.
    CrossrefPubMedGoogle Scholar
  • 28 Martin-Paredero V, Vadillo J, Diaz J. et al. Fibrinogen and fibrinolysis in blood and in the arterial wall: its role in advanced atherosclerotic disease. Cardiovasc Surg 1998; 06: 457-462.
    CrossrefPubMedGoogle Scholar
  • 29 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262: 157-172.
    CrossrefPubMedGoogle Scholar
  • 30 Lemkes BA, Hermanides J, Devries JH. et al. Hyperglycaemia: a prothrombotic factor?. J Thromb Haemost 2010; 08: 1663-1669.
    CrossrefPubMedGoogle Scholar
  • 31 Hajjar KA, Jacovina AT, Chacko J. An endothelial cell receptor for plasminogen/ tissue plasminogen activator. I. Identity with annexin II. J Biol Chem 1994; 269: 21191-21197.
    PubMedGoogle Scholar
  • 32 Cesarman GM, Guevara CA, Hajjar KA. An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA). II. Annexin II-mediated enhancement of t-PA-dependent plasminogen activation. J Biol Chem 1994; 269: 21198-21203.
    PubMedGoogle Scholar
  • 33 Pandolfi A, Iacoviello L, Capani F. et al. Glucose and insulin independently reduce the fibrinolytic potential of human vascular smooth muscle cells in culture. Diabetologia 1996; 39: 1425-1431.
    CrossrefPubMedGoogle Scholar
  • 34 Ziegler O, Drouin P. Haemobiological activity of gliclazide in diabetes mellitus. Diabetes Res Clin Pract 1991; 14 (Suppl. 02) S83-S89.
    CrossrefPubMedGoogle Scholar
  • 35 Pandolfi A, Giaccari A, Cilli C. et al. Acute hyperglycaemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat. Acta Diabetol 2001; 38: 71-76.
    CrossrefPubMedGoogle Scholar
  • 36 Choi KS, Fitzpatrick SL, Filipenko NR. et al. Regulation of plasmin-dependent fibrin clot lysis by annexin II heterotetramer. J Biol Chem 2001; 276: 25212-25221.
    CrossrefPubMedGoogle Scholar
  • 37 He KL, Deora AB, Xiong H. et al. Endothelial cell annexin A2 regulates polyubiquitination and degradation of its binding partner S100A10/p11. J Biol Chem 2008; 283: 19192-19200.
    CrossrefPubMedGoogle Scholar
  • 38 Hajjar KA, Krishnan S. Annexin II: a mediator of the plasmin/plasminogen activator system. Trends Cardiovasc Med 1999; 09: 128-138.
    CrossrefPubMedGoogle Scholar
  • 39 Dejouvencel T, Doeuvre L, Lacroix R. et al. Fibrinolytic cross-talk: a new mechanism for plasmin formation. Blood 2010; 115: 2048-2056.
    CrossrefPubMedGoogle Scholar
  • 40 He KL, Sui G, Xiong H. et al. Feedback regulation of endothelial cell surface plasmin generation by PKC-dependent phosphorylation of annexin A2. J Biol Chem 2011; 286: 15428-15439.
    CrossrefPubMedGoogle Scholar
  • 41 Eitzman DT, Westrick RJ, Xu Z. et al. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood 2000; 96: 4212-4215.
    PubMedGoogle Scholar