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Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity
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Ajjan, R. A., Gamlen, T., Standeven, K. F., Mughal, S., Hess, K., Smith, K. A., Dunn, E. J., Anwar, M. M., Rabbani, Naila, Thornalley, Paul J., Philippou, H. and Grant, P. J. (2013) Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity. Blood, Volume 122 (Number 1). pp. 134-142. doi:10.1182/blood-2013-04-494641
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Official URL: http://dx.doi.org/10.1182/blood-2013-04-494641
Abstract
Diabetes is associated with hypofibrinolysis by mechanisms that are only partially understood. We investigated the effects of in vivo plasminogen glycation on fibrinolysis, plasmin generation, protein proteolytic activity, and plasminogen-fibrin interactions. Plasma was collected from healthy controls and individuals with type 1 diabetes before and after improving glycemia. Plasma-purified plasmin(ogen) functional activity was evaluated by chromogenic, turbidimetric, and plasmin conversion assays, with surface plasmon resonance employed for fibrin-plasminogen interactions. Plasminogen post-translational modifications were quantified by mass spectrometry and glycation sites located by peptide mapping. Diabetes was associated with impaired plasma fibrin network lysis, which partly normalized upon improving glycaemia. Purified plasmin (ogen) from diabetic subjects had impaired fibrinolytic activity compared with controls (723 +/- 16 and 317 +/- 4 s, respectively; P < .01), mainly related to decreased fibrin-dependent plasmin generation and reduced protease activity (K-cat/K-M 2.57 +/- 1.02 x 10(-3) and 5.67 +/- 0.98 x 10(-3) M-1 s(-1), respectively; P < .05). N epsilon-fructosyl-lysine residue on plasminogen was increased in diabetes compared with controls (6.26 +/- 3.43 and 1.82 +/- 0.95%mol, respectively; P < .01) with preferential glycation of lysines 107 and 557, sites involved in fibrin binding and plasmin(ogen) cleavage, respectively. Glycation of plasminogen in diabetes directly affects fibrinolysis by decreasing plasmin generation and reducing protein-specific activity, changes that are reversible with modest improvement in glycemic control.
| Item Type: | Journal Article | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||||||
| Journal or Publication Title: | Blood | ||||||||
| Publisher: | American Society of Hematology | ||||||||
| ISSN: | 0006-4971 | ||||||||
| Official Date: | 4 July 2013 | ||||||||
| Dates: |
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| Volume: | Volume 122 | ||||||||
| Number: | Number 1 | ||||||||
| Page Range: | pp. 134-142 | ||||||||
| DOI: | 10.1182/blood-2013-04-494641 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published |
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