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Glycated proteins modulate tissue-plasminogen activator-catalyzed plasminogen activation
I W Bobbink1, W L Tekelenburg, J J Sixma
1Department of Haematology, University Hospital, Utrecht, The Netherlands.
Biochemical and Biophysical Research Communications
|December 17, 1997
Summary
Glycation of proteins like fibrin enhances tissue-plasminogen activator (t-PA) activity by increasing its affinity for these molecules. This process may contribute to extracellular matrix breakdown and affect fibrinolysis in diabetic patients.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Plasminogen activation by tissue-plasminogen activator (t-PA) is crucial for fibrinolysis.
- Macromolecular surfaces accelerate t-PA activity by templating enzyme and substrate.
- Glycation of proteins, common in diabetes, modifies lysine residues essential for this templating function.
Purpose of the Study:
- To investigate the impact of protein glycation on t-PA-catalyzed plasmin formation.
- To determine how glycated fibrin(ogen) affects t-PA and plasminogen binding and activation.
- To assess the influence of glycated proteins on plasminogen activator inhibitor-1 (PAI-1) and template function.
Main Methods:
- Studied plasminogen activation kinetics on glycated vs. non-glycated fibrin(ogen).
- Assessed binding affinities of t-PA and plasminogen to glycated and non-glycated substrates.
- Measured PAI-1 binding and activity on glycated fibrin.
- Investigated template function induction using immobilized glycated bovine serum albumin (BSA) and human gamma-globulins (IgG).
Main Results:
- Plasminogen activation was increased on glycated fibrin(ogen), primarily due to higher t-PA affinity.
- Plasminogen binding to glycated fibrin increased, but did not enhance activation.
- PAI-1 binding and activity were elevated on glycated fibrin.
- Template function was induced on immobilized glycated BSA and IgG.
Conclusions:
- Glycation enhances t-PA's template function on proteins like fibrin, leading to increased plasmin generation.
- Elevated plasmin generation at sites of glycated protein deposition may promote extracellular matrix breakdown.
- Soluble glycated proteins can inhibit t-PA binding and interfere with fibrinolysis in diabetic patients.