Glycated proteins modulate tissue-plasminogen activator-catalyzed plasminogen activation.
Plasminogen activation by tissue-plasminogen activator (t-PA) is accelerated by the presence of a macromolecular surface, which acts as a template that brings enzyme and substrate in close proximity. Modification of lysine residues, which are important for this template function, occurs in diabetic patients as a consequence of glycation of proteins. In this study, we investigated the effects of glycation of fibrin and other proteins in t-PA-catalyzed plasmin formation. Plasminogen activation on glycated fibrin(ogen) was increased compared to non-glycated fibrin(ogen), which could fully be attributed to an increased affinity of t-PA for glycated fibrin(ogen). Binding of plasminogen to glycated fibrin was increased, but did not contribute to increased plasminogen activation. Both plasminogen activator inhibitor-1 (PAI-1) binding and activity were increased on glycated fibrin. Induction of template function in plasminogen activation was also observed on immobilized glycated bovine serum albumin (BSA) and human gamma-globulins (IgG). Increased plasmin generation at sites of deposition of glycated proteins may lead to increased extracellular matrix breakdown and thereby affect the integrity of the endothelial monolayer. Moreover, soluble glycated BSA and glycated IgG can inhibit t-PA binding to immobilized glycated fibrin and interfere with fibrinolysis in diabetic patients.
Bobbink
I W
IW
Department of Haematology, University Hospital, Utrecht, The Netherlands.
Tekelenburg
W L
WL
Sixma
J J
JJ
de Boer
H C
HC
Banga
J D
JD
de Groot
P G
PG
D001667:Binding, Competitive; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005337:Fibrin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D005340:Fibrinogen / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D017127:Glycation End Products, Advanced; D006031:Glycosylation; D006801:Humans; D010958:Plasminogen / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D000093423:Glycated Serum Albumin
D017127:Glycation End Products, Advanced; D017395:Plasminogen Activator Inhibitor 1; D012709:Serum Albumin; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D000093423:Glycated Serum Albumin